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Preclinical Evaluation of 226Ac as a Theranostic Agent: Imaging, Dosimetry, and Therapy | Journal of Nuclear Medicine
<!DOCTYPE html> <html lang="en" dir="ltr" xmlns="http://www.w3.org/1999/xhtml" xmlns:mml="http://www.w3.org/1998/Math/MathML"> <head prefix="og: http://ogp.me/ns# article: http://ogp.me/ns/article# book: http://ogp.me/ns/book#" > <!--[if IE]><![endif]--> <link rel="dns-prefetch" href="//securepubads.g.doubleclick.net" /> <link rel="dns-prefetch" href="//scholar.google.com" /> <meta http-equiv="Content-Type" content="text/html; charset=utf-8" /> <link rel="shortcut icon" href="https://jnm.snmjournals.org/sites/default/files/images/favicon.ico" type="image/vnd.microsoft.icon" /> <meta name="viewport" content="width=device-width, initial-scale=1" /> <link rel="shortlink" href="/node/124318" /> <meta name="article_thumbnail" content="https://jnm.snmjournals.org/content/jnumed/65/11/1762/embed/icon-1.jpg" /> <meta name="issue_cover_image" content="https://jnm.snmjournals.org/sites/default/files/highwire/jnumed/65/11.cover-source.jpg" /> <meta name="type" content="article" /> <meta name="category" content="research-article" /> <meta name="HW.identifier" content="/jnumed/65/11/1762.atom" /> <meta name="HW.pisa" content="jnumed;65/11/1762" /> <meta name="DC.Format" content="text/html" /> <meta name="DC.Language" content="en" /> <meta name="DC.Title" content="Preclinical Evaluation of 226Ac as a Theranostic Agent: Imaging, Dosimetry, and Therapy" /> <meta name="DC.Identifier" content="10.2967/jnumed.124.267999" /> <meta name="DC.Date" content="2024-11-01" /> <meta name="DC.Publisher" content="Society of Nuclear Medicine" /> <meta name="DC.Rights" content="© 2024 by the Society of Nuclear Medicine and Molecular Imaging." /> <meta name="DC.AccessRights" content="restricted" /> <meta name="DC.Description" content="226Ac (t½ = 29.37 h) has been proposed as a theranostic radioisotope leveraging both its diagnostic γ-emissions and therapeutic α-emissions. 226Ac emits 158 and 230 keV γ-photons ideal for quantitative SPECT imaging and acts as an in vivo generator of 4 high-energy α-particles. Because of these nuclear decay properties, 226Ac has potential to act as a standalone theranostic isotope. In this proof-of-concept study, we evaluated a preclinical 226Ac-radiopharmaceutical for its theranostic efficacy and present the first 226Ac-targeted α-therapy study. Methods: 226Ac was produced at TRIUMF and labeled with the chelator-peptide bioconjugate crown-TATE. [226Ac]Ac-crown-TATE was selected to target neuroendocrine tumors in male NRG mice bearing AR42J tumor xenografts for SPECT imaging, biodistribution, and therapy studies. A preclinical SPECT/CT scanner acquired quantitative images reconstructed from both the 158 and the 230 keV emissions. Mice in the biodistribution study were euthanized at 1, 3, 5, 24, and 48 h after injection, and internal radiation dosimetry was derived for the tumor and organs of interest to establish appropriate therapeutic activity levels. Mice in the therapy study were administered 125, 250, or 375 kBq treatments and were monitored for tumor size and body condition. Results: We present quantitative SPECT images of the in vivo biodistribution of [226Ac]Ac-crown-TATE, which showed agreement with ex vivo measurements. Biodistribution studies demonstrated high uptake (>30%IA/g at 5 h after injection) and retention in the tumor, with an estimated mean absorbed dose coefficient of 222 mGy/kBq. [226Ac]Ac-crown-TATE treatments significantly extended the median survival from 7 d in the control groups to 16, 24, and 27 d in the 125, 250, and 375 kBq treatment groups, respectively. Survival was prolonged by slowing tumor growth, and no weight loss or toxicities were observed. Conclusion: This study highlights the theranostic potential of 226Ac as a standalone therapeutic isotope in addition to its demonstrated diagnostic capabilities to assess dosimetry in matched 225Ac-radiopharmaceuticals. Future studies will investigate maximum dose and toxicity to further explore the therapeutic potential of 226Ac-radiopharmaceuticals." /> <meta name="DC.Contributor" content="Helena Koniar" /> <meta name="DC.Contributor" content="Luke Wharton" /> <meta name="DC.Contributor" content="Aidan Ingham" /> <meta name="DC.Contributor" content="Ana Paulina Morales Oliver" /> <meta name="DC.Contributor" content="Helen Merkens" /> <meta name="DC.Contributor" content="Cristina Rodríguez-Rodríguez" /> <meta name="DC.Contributor" content="Peter Kunz" /> <meta name="DC.Contributor" content="Valery Radchenko" /> <meta name="DC.Contributor" content="Hua Yang" /> <meta name="DC.Contributor" content="Arman Rahmim" /> <meta name="DC.Contributor" content="Carlos Uribe" /> <meta name="DC.Contributor" content="Paul Schaffer" /> <meta name="article:published_time" content="2024-11-01" /> <meta name="article:section" content="FEATURED BASIC SCIENCE ARTICLE" /> <meta name="citation_title" content="Preclinical Evaluation of 226Ac as a Theranostic Agent: Imaging, Dosimetry, and Therapy" /> <meta name="citation_abstract" lang="en" content="<p><sup>226</sup>Ac (t<sub>½</sub> = 29.37 h) has been proposed as a theranostic radioisotope leveraging both its diagnostic γ-emissions and therapeutic α-emissions. <sup>226</sup>Ac emits 158 and 230 keV γ-photons ideal for quantitative SPECT imaging and acts as an in&nbsp;vivo generator of 4 high-energy α-particles. Because of these nuclear decay properties, <sup>226</sup>Ac has potential to act as a standalone theranostic isotope. In this proof-of-concept study, we evaluated a preclinical <sup>226</sup>Ac-radiopharmaceutical for its theranostic efficacy and present the first <sup>226</sup>Ac-targeted α-therapy study. <b>Methods:</b><sup>226</sup>Ac was produced at TRIUMF and labeled with the chelator-peptide bioconjugate crown-TATE. [<sup>226</sup>Ac]Ac-crown-TATE was selected to target neuroendocrine tumors in male NRG mice bearing AR42J tumor xenografts for SPECT imaging, biodistribution, and therapy studies. A preclinical SPECT/CT scanner acquired quantitative images reconstructed from both the 158 and the 230 keV emissions. Mice in the biodistribution study were euthanized at 1, 3, 5, 24, and 48 h after injection, and internal radiation dosimetry was derived for the tumor and organs of interest to establish appropriate therapeutic activity levels. Mice in the therapy study were administered 125, 250, or 375 kBq treatments and were monitored for tumor size and body condition. <b>Results:</b> We present quantitative SPECT images of the in&nbsp;vivo biodistribution of [<sup>226</sup>Ac]Ac-crown-TATE, which showed agreement with ex vivo measurements. Biodistribution studies demonstrated high uptake (&gt;30%IA/g at 5 h after injection) and retention in the tumor, with an estimated mean absorbed dose coefficient of 222 mGy/kBq. [<sup>226</sup>Ac]Ac-crown-TATE treatments significantly extended the median survival from 7 d in the control groups to 16, 24, and 27 d in the 125, 250, and 375 kBq treatment groups, respectively. Survival was prolonged by slowing tumor growth, and no weight loss or toxicities were observed. <b>Conclusion:</b> This study highlights the theranostic potential of <sup>226</sup>Ac as a standalone therapeutic isotope in addition to its demonstrated diagnostic capabilities to assess dosimetry in matched <sup>225</sup>Ac-radiopharmaceuticals. Future studies will investigate maximum dose and toxicity to further explore the therapeutic potential of <sup>226</sup>Ac-radiopharmaceuticals.</p>" /> <meta name="citation_abstract" lang="en" scheme="graphical" content="<h3>Visual Abstract</h3> " /> <meta name="citation_journal_title" content="Journal of Nuclear Medicine" /> <meta name="citation_publisher" content="Society of Nuclear Medicine" /> <meta name="citation_publication_date" content="2024/11/01" /> <meta name="citation_mjid" content="jnumed;65/11/1762" /> <meta name="citation_id" content="65/11/1762" /> <meta name="citation_public_url" content="https://jnm.snmjournals.org/content/65/11/1762" /> <meta name="citation_abstract_html_url" content="https://jnm.snmjournals.org/content/65/11/1762.abstract" /> <meta name="citation_full_html_url" content="https://jnm.snmjournals.org/content/65/11/1762.full" /> <meta name="citation_pdf_url" content="https://jnm.snmjournals.org/content/jnumed/65/11/1762.full.pdf" /> <meta name="citation_issn" content="0161-5505" /> <meta name="citation_issn" content="2159-662X" /> <meta name="citation_doi" content="10.2967/jnumed.124.267999" /> <meta name="citation_pmid" content="39362766" /> <meta name="citation_volume" content="65" /> <meta name="citation_issue" content="11" /> <meta name="citation_num_pages" content="7" /> <meta name="citation_article_type" content="Research Article" /> <meta name="citation_section" content="FEATURED BASIC SCIENCE ARTICLE" /> <meta name="citation_firstpage" content="1762" /> <meta name="citation_lastpage" content="1768" /> <meta name="citation_author" content="Helena Koniar" /> <meta name="citation_author_institution" content="Life Sciences Division, TRIUMF, Vancouver, British Columbia, Canada;" /> <meta name="citation_author_institution" content="Department of Physics and Astronomy, University of British Columbia, Vancouver, British Columbia, Canada;" /> <meta name="citation_author" content="Luke Wharton" /> <meta name="citation_author_institution" content="Life Sciences Division, TRIUMF, Vancouver, British Columbia, Canada;" /> <meta name="citation_author" content="Aidan Ingham" /> <meta name="citation_author_institution" content="Life Sciences Division, TRIUMF, Vancouver, British Columbia, Canada;" /> <meta name="citation_author" content="Ana Paulina Morales Oliver" /> <meta name="citation_author_institution" content="Life Sciences Division, TRIUMF, Vancouver, British Columbia, Canada;" /> <meta name="citation_author_institution" content="Accelerator Division, TRIUMF, Vancouver, British Columbia, Canada;" /> <meta name="citation_author" content="Helen Merkens" /> <meta name="citation_author_institution" content="BC Cancer Research Centre, Vancouver, British Columbia, Canada;" /> <meta name="citation_author" content="Cristina Rodríguez-Rodríguez" /> <meta name="citation_author_institution" content="Department of Physics and Astronomy, University of British Columbia, Vancouver, British Columbia, Canada;" /> <meta name="citation_author_institution" content="Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada;" /> <meta name="citation_author" content="Peter Kunz" /> <meta name="citation_author_institution" content="Accelerator Division, TRIUMF, Vancouver, British Columbia, Canada;" /> <meta name="citation_author_institution" content="Department of Chemistry, Simon Fraser University, Burnaby, British Columbia, Canada;" /> <meta name="citation_author" content="Valery Radchenko" /> <meta name="citation_author_institution" content="Life Sciences Division, TRIUMF, Vancouver, British Columbia, Canada;" /> <meta name="citation_author_institution" content="Department of Chemistry, University of British Columbia, Vancouver, British Columbia, Canada;" /> <meta name="citation_author" content="Hua Yang" /> <meta name="citation_author_institution" content="Life Sciences Division, TRIUMF, Vancouver, British Columbia, Canada;" /> <meta name="citation_author_institution" content="Department of Chemistry, Simon Fraser University, Burnaby, British Columbia, Canada;" /> <meta name="citation_author" content="Arman Rahmim" /> <meta name="citation_author_institution" content="Department of Physics and Astronomy, University of British Columbia, Vancouver, British Columbia, Canada;" /> <meta name="citation_author_institution" content="BC Cancer Research Centre, Vancouver, British Columbia, Canada;" /> <meta name="citation_author_institution" content="Department of Radiology, University of British Columbia, Vancouver, British Columbia, Canada; 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McCutchan;citation_title=Nuclear data sheets for A = 212;citation_pages=117-267;citation_volume=168;citation_year=2020" /> <meta name="citation_reference" content="citation_journal_title=Pharmaceuticals (Basel).;citation_author=RM. de Kruijff;citation_author=HT. Wolterbeek;citation_author=AG. Denkova;citation_title=A critical review of alpha radionuclide therapy: how to deal with recoiling daughters?;citation_pages=321-336;citation_volume=8;citation_year=2015;citation_pmid=26066613" /> <meta name="citation_reference" content="citation_journal_title=Pharmaceutics.;citation_author=CN. Funeh;citation_author=J. Bridoux;citation_author=T. Ertveldt;citation_title=Optimizing the safety and efficacy of bio-radiopharmaceuticals for cancer therapy;citation_pages=1378;citation_volume=15;citation_year=2023;citation_pmid=37242621" /> <meta name="twitter:title" content="Preclinical Evaluation of 226Ac as a Theranostic Agent: Imaging, Dosimetry, and Therapy" /> <meta name="twitter:card" content="summary_large_image" /> <meta name="twitter:image" content="https://jnm.snmjournals.org/sites/default/files/highwire/jnumed/65/11.cover-source.jpg" /> <meta name="twitter:description" content="226Ac (t½ = 29.37 h) has been proposed as a theranostic radioisotope leveraging both its diagnostic γ-emissions and therapeutic α-emissions. 226Ac emits 158 and 230 keV γ-photons ideal for quantitative SPECT imaging and acts as an in vivo generator of 4 high-energy α-particles. Because of these nuclear decay properties, 226Ac has potential to act as a standalone theranostic isotope. In this proof-of-concept study, we evaluated a preclinical 226Ac-radiopharmaceutical for its theranostic efficacy and present the first 226Ac-targeted α-therapy study. Methods: 226Ac was produced at TRIUMF and labeled with the chelator-peptide bioconjugate crown-TATE. [226Ac]Ac-crown-TATE was selected to target neuroendocrine tumors in male NRG mice bearing AR42J tumor xenografts for SPECT imaging, biodistribution, and therapy studies. A preclinical SPECT/CT scanner acquired quantitative images reconstructed from both the 158 and the 230 keV emissions. Mice in the biodistribution study were euthanized at 1, 3, 5, 24, and 48 h after injection, and internal radiation dosimetry was derived for the tumor and organs of interest to establish appropriate therapeutic activity levels. Mice in the therapy study were administered 125, 250, or 375 kBq treatments and were monitored for tumor size and body condition. Results: We present quantitative SPECT images of the in vivo biodistribution of [226Ac]Ac-crown-TATE, which showed agreement with ex vivo measurements. Biodistribution studies demonstrated high uptake (>30%IA/g at 5 h after injection) and retention in the tumor, with an estimated mean absorbed dose coefficient of 222 mGy/kBq. [226Ac]Ac-crown-TATE treatments significantly extended the median survival from 7 d in the control groups to 16, 24, and 27 d in the 125, 250, and 375 kBq treatment groups, respectively. Survival was prolonged by slowing tumor growth, and no weight loss or toxicities were observed. Conclusion: This study highlights the theranostic potential of 226Ac as a standalone therapeutic isotope in addition to its demonstrated diagnostic capabilities to assess dosimetry in matched 225Ac-radiopharmaceuticals. Future studies will investigate maximum dose and toxicity to further explore the therapeutic potential of 226Ac-radiopharmaceuticals." /> <meta name="og-title" property="og:title" content="Preclinical Evaluation of 226Ac as a Theranostic Agent: Imaging, Dosimetry, and Therapy" /> <meta name="og-url" property="og:url" content="https://jnm.snmjournals.org/content/65/11/1762" /> <meta name="og-site-name" property="og:site_name" content="Journal of Nuclear Medicine" /> <meta name="og-description" property="og:description" content="226Ac (t½ = 29.37 h) has been proposed as a theranostic radioisotope leveraging both its diagnostic γ-emissions and therapeutic α-emissions. 226Ac emits 158 and 230 keV γ-photons ideal for quantitative SPECT imaging and acts as an in vivo generator of 4 high-energy α-particles. Because of these nuclear decay properties, 226Ac has potential to act as a standalone theranostic isotope. In this proof-of-concept study, we evaluated a preclinical 226Ac-radiopharmaceutical for its theranostic efficacy and present the first 226Ac-targeted α-therapy study. Methods: 226Ac was produced at TRIUMF and labeled with the chelator-peptide bioconjugate crown-TATE. [226Ac]Ac-crown-TATE was selected to target neuroendocrine tumors in male NRG mice bearing AR42J tumor xenografts for SPECT imaging, biodistribution, and therapy studies. A preclinical SPECT/CT scanner acquired quantitative images reconstructed from both the 158 and the 230 keV emissions. Mice in the biodistribution study were euthanized at 1, 3, 5, 24, and 48 h after injection, and internal radiation dosimetry was derived for the tumor and organs of interest to establish appropriate therapeutic activity levels. Mice in the therapy study were administered 125, 250, or 375 kBq treatments and were monitored for tumor size and body condition. Results: We present quantitative SPECT images of the in vivo biodistribution of [226Ac]Ac-crown-TATE, which showed agreement with ex vivo measurements. Biodistribution studies demonstrated high uptake (>30%IA/g at 5 h after injection) and retention in the tumor, with an estimated mean absorbed dose coefficient of 222 mGy/kBq. [226Ac]Ac-crown-TATE treatments significantly extended the median survival from 7 d in the control groups to 16, 24, and 27 d in the 125, 250, and 375 kBq treatment groups, respectively. Survival was prolonged by slowing tumor growth, and no weight loss or toxicities were observed. Conclusion: This study highlights the theranostic potential of 226Ac as a standalone therapeutic isotope in addition to its demonstrated diagnostic capabilities to assess dosimetry in matched 225Ac-radiopharmaceuticals. Future studies will investigate maximum dose and toxicity to further explore the therapeutic potential of 226Ac-radiopharmaceuticals." /> <meta name="og-type" property="og:type" content="article" /> <meta name="og-image" property="og:image" content="https://jnm.snmjournals.org/sites/default/files/highwire/jnumed/65/11.cover-source.jpg" /> <link rel="canonical" href="https://jnm.snmjournals.org/content/65/11/1762" /> <meta name="Generator" content="Drupal 7 (http://drupal.org)" /> <link rel="alternate" type="application/pdf" title="Full Text (PDF)" href="/content/65/11/1762.full.pdf" /> <link rel="alternate" type="text/plain" title="Full Text (Plain)" href="/content/65/11/1762.full.txt" /> <link rel="alternate" type="application/vnd.ms-powerpoint" title="Powerpoint" href="/content/65/11/1762.ppt" /> <title>Preclinical Evaluation of 226Ac as a Theranostic Agent: Imaging, Dosimetry, and Therapy | Journal of Nuclear Medicine</title> <link type="text/css" rel="stylesheet" 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style="background:url('/sites/all/modules/contrib/gtranslate/gtranslate-files/16l.png') no-repeat scroll 0 -576px;padding-left:18px;">Estonian</option><option value="en|tl" style="background:url('/sites/all/modules/contrib/gtranslate/gtranslate-files/16l.png') no-repeat scroll 0 -400px;padding-left:18px;">Filipino</option><option value="en|fi" style="background:url('/sites/all/modules/contrib/gtranslate/gtranslate-files/16l.png') no-repeat scroll 0 -144px;padding-left:18px;">Finnish</option><option value="en|fr" style="background:url('/sites/all/modules/contrib/gtranslate/gtranslate-files/16l.png') no-repeat scroll 0 -160px;padding-left:18px;">French</option><option value="en|fy" style="background:url('/sites/all/modules/contrib/gtranslate/gtranslate-files/16l.png') no-repeat scroll 0 -1632px;padding-left:18px;">Frisian</option><option value="en|gl" style="background:url('/sites/all/modules/contrib/gtranslate/gtranslate-files/16l.png') no-repeat scroll 0 -592px;padding-left:18px;">Galician</option><option value="en|ka" style="background:url('/sites/all/modules/contrib/gtranslate/gtranslate-files/16l.png') no-repeat scroll 0 -880px;padding-left:18px;">Georgian</option><option value="en|de" style="background:url('/sites/all/modules/contrib/gtranslate/gtranslate-files/16l.png') no-repeat scroll 0 -176px;padding-left:18px;">German</option><option value="en|el" style="background:url('/sites/all/modules/contrib/gtranslate/gtranslate-files/16l.png') no-repeat scroll 0 -192px;padding-left:18px;">Greek</option><option value="en|gu" style="background:url('/sites/all/modules/contrib/gtranslate/gtranslate-files/16l.png') no-repeat scroll 0 -992px;padding-left:18px;">Gujarati</option><option value="en|ht" style="background:url('/sites/all/modules/contrib/gtranslate/gtranslate-files/16l.png') no-repeat scroll 0 -896px;padding-left:18px;">Haitian Creole</option><option value="en|ha" style="background:url('/sites/all/modules/contrib/gtranslate/gtranslate-files/16l.png') no-repeat scroll 0 -1008px;padding-left:18px;">Hausa</option><option value="en|haw" style="background:url('/sites/all/modules/contrib/gtranslate/gtranslate-files/16l.png') no-repeat scroll 0 -1488px;padding-left:18px;">Hawaiian</option><option value="en|iw" style="background:url('/sites/all/modules/contrib/gtranslate/gtranslate-files/16l.png') no-repeat scroll 0 -416px;padding-left:18px;">Hebrew</option><option value="en|hi" style="background:url('/sites/all/modules/contrib/gtranslate/gtranslate-files/16l.png') no-repeat scroll 0 -208px;padding-left:18px;">Hindi</option><option value="en|hmn" style="background:url('/sites/all/modules/contrib/gtranslate/gtranslate-files/16l.png') no-repeat scroll 0 -1024px;padding-left:18px;">Hmong</option><option value="en|hu" style="background:url('/sites/all/modules/contrib/gtranslate/gtranslate-files/16l.png') no-repeat scroll 0 -608px;padding-left:18px;">Hungarian</option><option value="en|is" style="background:url('/sites/all/modules/contrib/gtranslate/gtranslate-files/16l.png') no-repeat scroll 0 -784px;padding-left:18px;">Icelandic</option><option value="en|ig" style="background:url('/sites/all/modules/contrib/gtranslate/gtranslate-files/16l.png') no-repeat scroll 0 -1040px;padding-left:18px;">Igbo</option><option value="en|id" style="background:url('/sites/all/modules/contrib/gtranslate/gtranslate-files/16l.png') no-repeat scroll 0 -432px;padding-left:18px;">Indonesian</option><option value="en|ga" style="background:url('/sites/all/modules/contrib/gtranslate/gtranslate-files/16l.png') no-repeat scroll 0 -736px;padding-left:18px;">Irish</option><option value="en|it" style="background:url('/sites/all/modules/contrib/gtranslate/gtranslate-files/16l.png') no-repeat scroll 0 -224px;padding-left:18px;">Italian</option><option value="en|ja" style="background:url('/sites/all/modules/contrib/gtranslate/gtranslate-files/16l.png') no-repeat scroll 0 -240px;padding-left:18px;">Japanese</option><option value="en|jw" style="background:url('/sites/all/modules/contrib/gtranslate/gtranslate-files/16l.png') no-repeat scroll 0 -1056px;padding-left:18px;">Javanese</option><option value="en|kn" style="background:url('/sites/all/modules/contrib/gtranslate/gtranslate-files/16l.png') no-repeat scroll 0 -1072px;padding-left:18px;">Kannada</option><option value="en|kk" style="background:url('/sites/all/modules/contrib/gtranslate/gtranslate-files/16l.png') no-repeat scroll 0 -1328px;padding-left:18px;">Kazakh</option><option value="en|km" style="background:url('/sites/all/modules/contrib/gtranslate/gtranslate-files/16l.png') no-repeat scroll 0 -1088px;padding-left:18px;">Khmer</option><option value="en|ko" style="background:url('/sites/all/modules/contrib/gtranslate/gtranslate-files/16l.png') no-repeat scroll 0 -256px;padding-left:18px;">Korean</option><option value="en|ku" style="background:url('/sites/all/modules/contrib/gtranslate/gtranslate-files/16l.png') no-repeat scroll 0 -1504px;padding-left:18px;">Kurdish (Kurmanji)</option><option value="en|ky" style="background:url('/sites/all/modules/contrib/gtranslate/gtranslate-files/16l.png') no-repeat scroll 0 -1520px;padding-left:18px;">Kyrgyz</option><option value="en|lo" style="background:url('/sites/all/modules/contrib/gtranslate/gtranslate-files/16l.png') no-repeat scroll 0 -1104px;padding-left:18px;">Lao</option><option value="en|la" style="background:url('/sites/all/modules/contrib/gtranslate/gtranslate-files/16l.png') no-repeat scroll 0 -1120px;padding-left:18px;">Latin</option><option value="en|lv" style="background:url('/sites/all/modules/contrib/gtranslate/gtranslate-files/16l.png') no-repeat scroll 0 -448px;padding-left:18px;">Latvian</option><option value="en|lt" style="background:url('/sites/all/modules/contrib/gtranslate/gtranslate-files/16l.png') no-repeat scroll 0 -464px;padding-left:18px;">Lithuanian</option><option value="en|lb" style="background:url('/sites/all/modules/contrib/gtranslate/gtranslate-files/16l.png') no-repeat scroll 0 -1536px;padding-left:18px;">Luxembourgish</option><option value="en|mk" style="background:url('/sites/all/modules/contrib/gtranslate/gtranslate-files/16l.png') no-repeat scroll 0 -800px;padding-left:18px;">Macedonian</option><option value="en|mg" style="background:url('/sites/all/modules/contrib/gtranslate/gtranslate-files/16l.png') no-repeat scroll 0 -1344px;padding-left:18px;">Malagasy</option><option value="en|ms" style="background:url('/sites/all/modules/contrib/gtranslate/gtranslate-files/16l.png') no-repeat scroll 0 -704px;padding-left:18px;">Malay</option><option value="en|ml" style="background:url('/sites/all/modules/contrib/gtranslate/gtranslate-files/16l.png') no-repeat scroll 0 -1360px;padding-left:18px;">Malayalam</option><option value="en|mt" style="background:url('/sites/all/modules/contrib/gtranslate/gtranslate-files/16l.png') no-repeat scroll 0 -624px;padding-left:18px;">Maltese</option><option value="en|mi" style="background:url('/sites/all/modules/contrib/gtranslate/gtranslate-files/16l.png') no-repeat scroll 0 -1136px;padding-left:18px;">Maori</option><option value="en|mr" style="background:url('/sites/all/modules/contrib/gtranslate/gtranslate-files/16l.png') no-repeat scroll 0 -1152px;padding-left:18px;">Marathi</option><option value="en|mn" style="background:url('/sites/all/modules/contrib/gtranslate/gtranslate-files/16l.png') no-repeat scroll 0 -1168px;padding-left:18px;">Mongolian</option><option value="en|my" style="background:url('/sites/all/modules/contrib/gtranslate/gtranslate-files/16l.png') no-repeat scroll 0 -1296px;padding-left:18px;">Myanmar (Burmese)</option><option value="en|ne" style="background:url('/sites/all/modules/contrib/gtranslate/gtranslate-files/16l.png') no-repeat scroll 0 -1184px;padding-left:18px;">Nepali</option><option value="en|no" style="background:url('/sites/all/modules/contrib/gtranslate/gtranslate-files/16l.png') no-repeat scroll 0 -272px;padding-left:18px;">Norwegian</option><option value="en|ps" style="background:url('/sites/all/modules/contrib/gtranslate/gtranslate-files/16l.png') no-repeat scroll 0 -1552px;padding-left:18px;">Pashto</option><option value="en|fa" style="background:url('/sites/all/modules/contrib/gtranslate/gtranslate-files/16l.png') no-repeat scroll 0 -672px;padding-left:18px;">Persian</option><option value="en|pl" style="background:url('/sites/all/modules/contrib/gtranslate/gtranslate-files/16l.png') no-repeat scroll 0 -288px;padding-left:18px;">Polish</option><option value="en|pt" style="background:url('/sites/all/modules/contrib/gtranslate/gtranslate-files/16l.png') no-repeat scroll 0 -304px;padding-left:18px;">Portuguese</option><option value="en|pa" style="background:url('/sites/all/modules/contrib/gtranslate/gtranslate-files/16l.png') no-repeat scroll 0 -1200px;padding-left:18px;">Punjabi</option><option value="en|ro" style="background:url('/sites/all/modules/contrib/gtranslate/gtranslate-files/16l.png') no-repeat scroll 0 -320px;padding-left:18px;">Romanian</option><option value="en|ru" style="background:url('/sites/all/modules/contrib/gtranslate/gtranslate-files/16l.png') no-repeat scroll 0 -336px;padding-left:18px;">Russian</option><option value="en|sm" style="background:url('/sites/all/modules/contrib/gtranslate/gtranslate-files/16l.png') no-repeat scroll 0 -1568px;padding-left:18px;">Samoan</option><option value="en|gd" style="background:url('/sites/all/modules/contrib/gtranslate/gtranslate-files/16l.png') no-repeat scroll 0 -1584px;padding-left:18px;">Scottish Gaelic</option><option value="en|sr" style="background:url('/sites/all/modules/contrib/gtranslate/gtranslate-files/16l.png') no-repeat scroll 0 -480px;padding-left:18px;">Serbian</option><option value="en|st" style="background:url('/sites/all/modules/contrib/gtranslate/gtranslate-files/16l.png') no-repeat scroll 0 -1392px;padding-left:18px;">Sesotho</option><option value="en|sn" style="background:url('/sites/all/modules/contrib/gtranslate/gtranslate-files/16l.png') no-repeat scroll 0 -1600px;padding-left:18px;">Shona</option><option value="en|sd" style="background:url('/sites/all/modules/contrib/gtranslate/gtranslate-files/16l.png') no-repeat scroll 0 -1616px;padding-left:18px;">Sindhi</option><option value="en|si" style="background:url('/sites/all/modules/contrib/gtranslate/gtranslate-files/16l.png') no-repeat scroll 0 -1376px;padding-left:18px;">Sinhala</option><option value="en|sk" style="background:url('/sites/all/modules/contrib/gtranslate/gtranslate-files/16l.png') no-repeat scroll 0 -496px;padding-left:18px;">Slovak</option><option value="en|sl" style="background:url('/sites/all/modules/contrib/gtranslate/gtranslate-files/16l.png') no-repeat scroll 0 -512px;padding-left:18px;">Slovenian</option><option value="en|so" style="background:url('/sites/all/modules/contrib/gtranslate/gtranslate-files/16l.png') no-repeat scroll 0 -1216px;padding-left:18px;">Somali</option><option value="en|es" style="background:url('/sites/all/modules/contrib/gtranslate/gtranslate-files/16l.png') no-repeat scroll 0 -352px;padding-left:18px;">Spanish</option><option value="en|su" style="background:url('/sites/all/modules/contrib/gtranslate/gtranslate-files/16l.png') no-repeat scroll 0 -1408px;padding-left:18px;">Sudanese</option><option value="en|sw" style="background:url('/sites/all/modules/contrib/gtranslate/gtranslate-files/16l.png') no-repeat scroll 0 -720px;padding-left:18px;">Swahili</option><option value="en|sv" style="background:url('/sites/all/modules/contrib/gtranslate/gtranslate-files/16l.png') no-repeat scroll 0 -368px;padding-left:18px;">Swedish</option><option value="en|tg" style="background:url('/sites/all/modules/contrib/gtranslate/gtranslate-files/16l.png') no-repeat scroll 0 -1424px;padding-left:18px;">Tajik</option><option value="en|ta" style="background:url('/sites/all/modules/contrib/gtranslate/gtranslate-files/16l.png') no-repeat scroll 0 -1232px;padding-left:18px;">Tamil</option><option value="en|te" style="background:url('/sites/all/modules/contrib/gtranslate/gtranslate-files/16l.png') no-repeat scroll 0 -1248px;padding-left:18px;">Telugu</option><option value="en|th" style="background:url('/sites/all/modules/contrib/gtranslate/gtranslate-files/16l.png') no-repeat scroll 0 -640px;padding-left:18px;">Thai</option><option value="en|tr" style="background:url('/sites/all/modules/contrib/gtranslate/gtranslate-files/16l.png') no-repeat scroll 0 -656px;padding-left:18px;">Turkish</option><option value="en|uk" style="background:url('/sites/all/modules/contrib/gtranslate/gtranslate-files/16l.png') no-repeat scroll 0 -528px;padding-left:18px;">Ukrainian</option><option value="en|ur" style="background:url('/sites/all/modules/contrib/gtranslate/gtranslate-files/16l.png') no-repeat scroll 0 -912px;padding-left:18px;">Urdu</option><option value="en|uz" style="background:url('/sites/all/modules/contrib/gtranslate/gtranslate-files/16l.png') no-repeat scroll 0 -1440px;padding-left:18px;">Uzbek</option><option value="en|vi" style="background:url('/sites/all/modules/contrib/gtranslate/gtranslate-files/16l.png') no-repeat scroll 0 -544px;padding-left:18px;">Vietnamese</option><option value="en|cy" style="background:url('/sites/all/modules/contrib/gtranslate/gtranslate-files/16l.png') no-repeat scroll 0 -752px;padding-left:18px;">Welsh</option><option value="en|xh" style="background:url('/sites/all/modules/contrib/gtranslate/gtranslate-files/16l.png') no-repeat scroll 0 -1648px;padding-left:18px;">Xhosa</option><option value="en|yi" style="background:url('/sites/all/modules/contrib/gtranslate/gtranslate-files/16l.png') no-repeat scroll 0 -816px;padding-left:18px;">Yiddish</option><option value="en|yo" style="background:url('/sites/all/modules/contrib/gtranslate/gtranslate-files/16l.png') no-repeat scroll 0 -1264px;padding-left:18px;">Yoruba</option><option value="en|zu" style="background:url('/sites/all/modules/contrib/gtranslate/gtranslate-files/16l.png') no-repeat scroll 0 -1280px;padding-left:18px;">Zulu</option></select> </div> </div> </div> </div> </div> </div> <div id="zone-menu" class="zone zone-menu clearfix mobile-hidden container-30"> <div class="grid-28 suffix-1 prefix-1 region region-menu region-menu-bg-opaque region-gutters-inner main-menu-active-bg" id="region-menu"> <div class="region-inner region-menu-inner"> <div class="block 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<a id="main-content"></a> <div class="block block-system block-main block-system-main odd block-without-title" id="block-system-main"> <div class="block-inner clearfix"> <div class="content clearfix"> <div class="panel-display panels-960-layout jcore-2col-layout" > <div class="panel-row-wrapper panel-row-first clearfix"> <div class="top-wrapper"> <div class="panel-panel panel-region-top"> <div class="inside"><div class="panel-pane pane-highwire-article-citation" > <div class="pane-content"> <div class="highwire-article-citation highwire-citation-type-highwire-article node124318--5" data-node-nid="124318" id="top-node-124318--6889594614" data-pisa="jnumed;65/11/1762" data-pisa-master="jnumed;jnumed.124.267999" data-apath="/jnumed/65/11/1762.atom" data-hw-author-tooltip-instance="highwire_author_tooltip"><div class="highwire-cite highwire-cite-highwire-article highwire-citation-jcore-article-title-complete clearfix has-author-tooltip highwire-citation-highwire-article-top-a"> <div class="highwire-cite-overline"><span class="highwire-cite-metadata-article-type highwire-cite-metadata">Research Article</span><span class="separator-pipe"></span><span class="highwire-cite-metadata-art-cat highwire-cite-metadata"><span class="wrapper">FEATURED BASIC SCIENCE ARTICLE</span></span></div> <div class="highwire-cite-access"><span class="highwire-citation-access highwire-citation-access-check" data-pisa-id="jnumed;jnumed.124.267999" data-atom-uri="/jnumed/65/11/1762.atom" data-request-view="full"></span></div> <h1 class="highwire-cite-title" id="page-title">Preclinical Evaluation of <sup>226</sup>Ac as a Theranostic Agent: Imaging, Dosimetry, and Therapy</h1> <div class="highwire-cite-authors"><span class="highwire-citation-authors"><span class="highwire-citation-author first" data-delta="0">Helena Koniar</span>, <span class="highwire-citation-author" data-delta="1">Luke Wharton</span>, <span class="highwire-citation-author" data-delta="2">Aidan Ingham</span>, <span class="highwire-citation-author" data-delta="3">Ana Paulina Morales Oliver</span>, <span class="highwire-citation-author" data-delta="4">Helen Merkens</span>, <span class="highwire-citation-author" data-delta="5">Cristina Rodríguez-Rodríguez</span>, <span class="highwire-citation-author" data-delta="6">Peter Kunz</span>, <span class="highwire-citation-author" data-delta="7">Valery Radchenko</span>, <span class="highwire-citation-author" data-delta="8">Hua Yang</span>, <span class="highwire-citation-author" data-delta="9">Arman Rahmim</span>, <span class="highwire-citation-author" data-delta="10">Carlos Uribe</span> and <span class="highwire-citation-author" data-delta="11">Paul Schaffer</span></span></div> <div class="highwire-cite-metadata"><span class="highwire-cite-metadata-journal highwire-cite-metadata">Journal of Nuclear Medicine </span><span class="highwire-cite-metadata-date highwire-cite-metadata">November 2024, </span><span class="highwire-cite-metadata-volume highwire-cite-metadata">65 </span><span class="highwire-cite-metadata-issue highwire-cite-metadata">(11) </span><span class="highwire-cite-metadata-pages highwire-cite-metadata">1762-1768; </span><span class="highwire-cite-metadata-doi highwire-cite-metadata">DOI: https://doi.org/10.2967/jnumed.124.267999 </span></div> <div class="highwire-cite-extras"><span class="highwire-foxycart-add-to-cart-ahah highwire-foxycart-add-to-cart-ahah" data-text="Add to Cart (%short-price)" data-apath="/jnumed/65/11/1762.atom" data-type="link" data-font-icon="" data-parent-id="124170"></span></div> </div> <div id="hw-article-author-popups-top-node-124318--6889594614" style="display: none;"><div class="author-tooltip-0"><div class="author-tooltip-name">Helena Koniar </div><div class="author-tooltip-affiliation"><span class="author-tooltip-text"><div class='author-affiliation'><span class='nlm-sup'>1</span>Life Sciences Division, TRIUMF, Vancouver, British Columbia, Canada;</div><div 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class="author-tooltip-name">Aidan Ingham </div><div class="author-tooltip-affiliation"><span class="author-tooltip-text"><div class='author-affiliation'><span class='nlm-sup'>1</span>Life Sciences Division, TRIUMF, Vancouver, British Columbia, Canada;</div></span></div><ul class="author-tooltip-find-more"><li class="author-tooltip-gs-link first"><a href="/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Aidan%2BIngham%2B" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on Google Scholar</a></li><li class="author-tooltip-pubmed-link"><a href="/lookup/external-ref?access_num=Ingham%20A&link_type=AUTHORSEARCH" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on PubMed</a></li><li class="author-site-search-link last"><a href="/search/author1%3AAidan%2BIngham%2B" rel="nofollow" class="" data-icon-position="" data-hide-link-title="0">Search for this author on this 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type-featured graphic-abstract odd"><div class="highwire-figure"><div class="fig-inline-img-wrapper"><div class="fig-inline-img"><a href="https://jnm.snmjournals.org/content/jnumed/65/11/1762/F1.large.jpg?width=800&height=600&carousel=1" title="" class="highwire-fragment fragment-images colorbox-load" rel="gallery-fragment-images-596830861" data-figure-caption="<div class="highwire-markup"></div>" data-icon-position="" data-hide-link-title="0"><span class="hw-responsive-img"><img class="highwire-fragment fragment-image lazyload" alt="Figure" src="data:image/gif;base64,R0lGODlhAQABAIAAAAAAAP///yH5BAEAAAAALAAAAAABAAEAAAIBRAA7" data-src="https://jnm.snmjournals.org/content/jnumed/65/11/1762/F1.medium.gif" width="440" height="219"/><noscript><img class="highwire-fragment fragment-image" alt="Figure" src="https://jnm.snmjournals.org/content/jnumed/65/11/1762/F1.medium.gif" width="440" height="219"/></noscript></span></a></div></div><ul class="highwire-figure-links inline"><li class="download-fig first"><a href="https://jnm.snmjournals.org/content/jnumed/65/11/1762/F1.large.jpg?download=true" class="highwire-figure-link highwire-figure-link-download" title="Download Figure1" data-icon-position="" data-hide-link-title="0">Download figure</a></li><li class="new-tab"><a href="https://jnm.snmjournals.org/content/jnumed/65/11/1762/F1.large.jpg" class="highwire-figure-link highwire-figure-link-newtab" target="_blank" data-icon-position="" data-hide-link-title="0">Open in new tab</a></li><li class="download-ppt last"><a href="/highwire/powerpoint/124193" class="highwire-figure-link highwire-figure-link-ppt" data-icon-position="" data-hide-link-title="0">Download powerpoint</a></li></ul></div></div><p id="p-2"></p></div><div class="section abstract" id="abstract-2"><h2>Abstract</h2><p id="p-3"><sup>226</sup>Ac (t<sub>½</sub> = 29.37 h) has been proposed as a theranostic radioisotope leveraging both its diagnostic γ-emissions and therapeutic α-emissions. <sup>226</sup>Ac emits 158 and 230 keV γ-photons ideal for quantitative SPECT imaging and acts as an in vivo generator of 4 high-energy α-particles. Because of these nuclear decay properties, <sup>226</sup>Ac has potential to act as a standalone theranostic isotope. In this proof-of-concept study, we evaluated a preclinical <sup>226</sup>Ac-radiopharmaceutical for its theranostic efficacy and present the first <sup>226</sup>Ac-targeted α-therapy study. <strong>Methods:</strong> <sup>226</sup>Ac was produced at TRIUMF and labeled with the chelator-peptide bioconjugate crown-TATE. [<sup>226</sup>Ac]Ac-crown-TATE was selected to target neuroendocrine tumors in male NRG mice bearing AR42J tumor xenografts for SPECT imaging, biodistribution, and therapy studies. A preclinical SPECT/CT scanner acquired quantitative images reconstructed from both the 158 and the 230 keV emissions. Mice in the biodistribution study were euthanized at 1, 3, 5, 24, and 48 h after injection, and internal radiation dosimetry was derived for the tumor and organs of interest to establish appropriate therapeutic activity levels. Mice in the therapy study were administered 125, 250, or 375 kBq treatments and were monitored for tumor size and body condition. <strong>Results:</strong> We present quantitative SPECT images of the in vivo biodistribution of [<sup>226</sup>Ac]Ac-crown-TATE, which showed agreement with ex vivo measurements. Biodistribution studies demonstrated high uptake (>30%IA/g at 5 h after injection) and retention in the tumor, with an estimated mean absorbed dose coefficient of 222 mGy/kBq. [<sup>226</sup>Ac]Ac-crown-TATE treatments significantly extended the median survival from 7 d in the control groups to 16, 24, and 27 d in the 125, 250, and 375 kBq treatment groups, respectively. Survival was prolonged by slowing tumor growth, and no weight loss or toxicities were observed. <strong>Conclusion:</strong> This study highlights the theranostic potential of <sup>226</sup>Ac as a standalone therapeutic isotope in addition to its demonstrated diagnostic capabilities to assess dosimetry in matched <sup>225</sup>Ac-radiopharmaceuticals. Future studies will investigate maximum dose and toxicity to further explore the therapeutic potential of <sup>226</sup>Ac-radiopharmaceuticals.</p></div><ul class="kwd-group"><li class="kwd"><a xmlns:default="http://www.w3.org/1999/xhtml" href="/keyword/226ac" class="hw-term hw-article-keyword hw-article-keyword-226ac" rel="nofollow"><sup xmlns:default="http://www.w3.org/1999/xhtml">226</sup>Ac</a></li><li class="kwd"><a href="/keyword/theranostics" class="hw-term hw-article-keyword hw-article-keyword-theranostics" rel="nofollow">theranostics</a></li><li class="kwd"><a href="/keyword/spect-imaging" class="hw-term hw-article-keyword hw-article-keyword-spect-imaging" rel="nofollow">SPECT imaging</a></li><li class="kwd"><a href="/keyword/targeted-%CE%B1-therapy" class="hw-term hw-article-keyword hw-article-keyword-targeted-α-therapy" rel="nofollow">targeted α-therapy</a></li><li class="kwd"><a href="/keyword/preclinical-radiopharmaceutical" class="hw-term hw-article-keyword hw-article-keyword-preclinical-radiopharmaceutical" rel="nofollow">preclinical radiopharmaceutical</a></li></ul><p id="p-4">Radiopharmaceutical therapy with α-emitters is advantageous for metastatic cancer patients by delivering a cytotoxic radiation dose directly to cancer cells while sparing healthy normal tissues (<a id="xref-ref-1-1" class="xref-bibr" href="#ref-1">1</a>,<a id="xref-ref-2-1" class="xref-bibr" href="#ref-2">2</a>). <sup>225</sup>Ac (t<sub>½</sub> = 9.92 d) radiopharmaceuticals have demonstrated promising preclinical and clinical outcomes, in part due to the emission of 4 α-particles throughout its decay chain (<a id="xref-ref-3-1" class="xref-bibr" href="#ref-3">3</a>–<a id="xref-ref-5-1" class="xref-bibr" href="#ref-5">5</a>). However, <sup>225</sup>Ac lacks direct imageable γ-emissions and can be detected and imaged only through γ-emissions released by its progeny radionuclides <sup>221</sup>Fr (t<sub>½</sub> = 4.80 min; 218 keV; 11.4%) and <sup>213</sup>Bi (t<sub>½</sub> = 45.6 min; 440 keV; 25.9%) (<a id="xref-ref-6-1" class="xref-bibr" href="#ref-6">6</a>,<a id="xref-ref-7-1" class="xref-bibr" href="#ref-7">7</a>). <sup>221</sup>Fr and <sup>213</sup>Bi detection occurs after multiple α-decays, which can introduce inaccuracies due to nuclear recoil and radiolysis of the radiopharmaceutical conjugate (<a id="xref-ref-8-1" class="xref-bibr" href="#ref-8">8</a>). Direct and quantitative detection of actinium in vivo could have significant benefits for both preclinical radiopharmaceutical development and clinical treatment plan optimization in patients.</p><p id="p-5"><sup>226</sup>Ac (t<sub>½</sub> = 29.37 h) is well suited to act as an element-equivalent matched theranostic pair with <sup>225</sup>Ac-radiopharmaceuticals (<a id="xref-fig-2-1" class="xref-fig" href="#F2">Fig. 1</a>). Element-equivalent theranostic pairs have the benefit of identical radiochemistry and pharmacokinetics in vivo (<a id="xref-ref-9-1" class="xref-bibr" href="#ref-9">9</a>–<a id="xref-ref-11-1" class="xref-bibr" href="#ref-11">11</a>). <sup>226</sup>Ac is imageable with SPECT through its 158 and 230 keV γ-emissions (<a id="xref-ref-12-1" class="xref-bibr" href="#ref-12">12</a>,<a id="xref-ref-13-1" class="xref-bibr" href="#ref-13">13</a>). Beyond its imaging applications, <sup>226</sup>Ac has also been proposed to act as a standalone therapeutic isotope by leveraging the α-emissions from its daughter <sup>226</sup>Th (<a id="xref-ref-14-1" class="xref-bibr" href="#ref-14">14</a>–<a id="xref-ref-16-1" class="xref-bibr" href="#ref-16">16</a>). <sup>226</sup>Ac β<sup>−</sup>-decays to <sup>226</sup>Th (t<sub>½</sub> = 30.6 min), which emits 4 high-energy α-particles with a cumulative 27.7 MeV through very short-lived (t<sub>½</sub> ≤ 38 s) progeny (<a id="xref-fig-2-2" class="xref-fig" href="#F2">Fig. 1</a>). <sup>226</sup>Th has previously been proposed as a therapeutic isotope generated through the decay of <sup>230</sup>U (<a id="xref-ref-15-1" class="xref-bibr" href="#ref-15">15</a>,<a id="xref-ref-17-1" class="xref-bibr" href="#ref-17">17</a>–<a id="xref-ref-19-1" class="xref-bibr" href="#ref-19">19</a>). However, to the best of our knowledge, no study has assessed the therapeutic efficacy of <sup>226</sup>Th.</p><div id="F2" class="fig pos-float odd"><div class="highwire-figure"><div class="fig-inline-img-wrapper"><div class="fig-inline-img"><a href="https://jnm.snmjournals.org/content/jnumed/65/11/1762/F2.large.jpg?width=800&height=600&carousel=1" title="226Ac decay chain and its physical properties. Photon emissions with branching ratios > 8% are shown." class="highwire-fragment fragment-images colorbox-load" rel="gallery-fragment-images-596830861" data-figure-caption="<div class="highwire-markup"><div xmlns="http://www.w3.org/1999/xhtml"><sup>226</sup>Ac decay chain and its physical properties. Photon emissions with branching ratios > 8% are shown.</div></div>" data-icon-position="" data-hide-link-title="0"><span class="hw-responsive-img"><img class="highwire-fragment fragment-image lazyload" alt="FIGURE 1." src="data:image/gif;base64,R0lGODlhAQABAIAAAAAAAP///yH5BAEAAAAALAAAAAABAAEAAAIBRAA7" data-src="https://jnm.snmjournals.org/content/jnumed/65/11/1762/F2.medium.gif" width="440" height="126"/><noscript><img class="highwire-fragment fragment-image" alt="FIGURE 1." src="https://jnm.snmjournals.org/content/jnumed/65/11/1762/F2.medium.gif" width="440" height="126"/></noscript></span></a></div></div><ul class="highwire-figure-links inline"><li class="download-fig first"><a href="https://jnm.snmjournals.org/content/jnumed/65/11/1762/F2.large.jpg?download=true" class="highwire-figure-link highwire-figure-link-download" title="Download FIGURE 1." data-icon-position="" data-hide-link-title="0">Download figure</a></li><li class="new-tab"><a href="https://jnm.snmjournals.org/content/jnumed/65/11/1762/F2.large.jpg" class="highwire-figure-link highwire-figure-link-newtab" target="_blank" data-icon-position="" data-hide-link-title="0">Open in new tab</a></li><li class="download-ppt last"><a href="/highwire/powerpoint/124282" class="highwire-figure-link highwire-figure-link-ppt" data-icon-position="" data-hide-link-title="0">Download powerpoint</a></li></ul></div><div class="fig-caption" xmlns:xhtml="http://www.w3.org/1999/xhtml"><span class="fig-label">FIGURE 1.</span> <p id="p-6" class="first-child"><sup>226</sup>Ac decay chain and its physical properties. Photon emissions with branching ratios > 8% are shown.</p><div class="sb-div caption-clear"></div></div></div><p id="p-7">The goal of this study was to assess the feasibility and demonstrate the proof-of-concept capabilities of <sup>226</sup>Ac to act as an independent standalone theranostic isotope with a preclinical radiopharmaceutical. The bioconjugate crown-TATE acts as an agonist to type 2 somatostatin receptors (SSTRs), which are overexpressed on the cell surfaces of advanced progressive neuroendocrine tumors (<a id="xref-ref-20-1" class="xref-bibr" href="#ref-20">20</a>). Previously, crown-TATE has been labeled with other radiometals, including <sup>155,161</sup>Tb and <sup>225</sup>Ac, and has demonstrated high tumor uptake and excellent in vivo stability (<a id="xref-ref-11-2" class="xref-bibr" href="#ref-11">11</a>,<a id="xref-ref-21-1" class="xref-bibr" href="#ref-21">21</a>). SSTRs are also expressed in many normal tissues and organs, including the gastrointestinal tract, pancreas, lungs, and kidneys. Because of this normal tissue expression, it is important to quantify accumulation and radiation dose to normal healthy tissues with SSTR-targeting radionuclide therapy. To the best of our knowledge, this was the first study to assess the therapeutic efficacy of <sup>226</sup>Ac. We evaluated the theranostic potential of [<sup>226</sup>Ac]Ac-crown-TATE in tumor-bearing mice through assessing its quantitative SPECT imaging performance, biodistribution profile, pharmacokinetics, internal radiation dosimetry to targeted tumors and healthy organs, and therapeutic tumor control.</p><div class="section materials-methods" id="sec-1"><h2 class="">MATERIALS AND METHODS</h2><div id="sec-2" class="subsection"><h3><sup>226</sup>Ac Production, Activity Quantification, and Radiolabeling</h3><p id="p-8"><sup>226</sup>Ac was produced at TRIUMF, Canada’s particle accelerator center, with the Isotope Separation and Acceleration facility which uses the isotope separation online method for producing radioactive ion beams (<a id="xref-ref-22-1" class="xref-bibr" href="#ref-22">22</a>,<a id="xref-ref-23-1" class="xref-bibr" href="#ref-23">23</a>). In total, 25.0 ± 2.0 MBq of <sup>226</sup>Ac were retrieved for this study. Crown-TATE was synthesized as described by Wharton et al. (<a id="xref-ref-11-3" class="xref-bibr" href="#ref-11">11</a>). Full descriptions of the <sup>226</sup>Ac production method, activity quantification, and radiolabeling procedures are presented in the supplemental materials (available at <a href="http://jnm.snmjournals.org">http://jnm.snmjournals.org</a>) (<a id="xref-ref-11-4" class="xref-bibr" href="#ref-11">11</a>,<a id="xref-ref-12-2" class="xref-bibr" href="#ref-12">12</a>,<a id="xref-ref-22-2" class="xref-bibr" href="#ref-22">22</a>–<a id="xref-ref-25-1" class="xref-bibr" href="#ref-25">25</a>).</p></div><div id="sec-3" class="subsection"><h3>Animal Model</h3><p id="p-9">Male NRG mice were obtained from the Department of Molecular Oncology at BC Cancer Research Centre. Mice were inoculated with approximately 6.5 × 10<sup>6</sup> cells from the AR42J tumor cell line via subcutaneous injection in the left shoulder. Tumors grew for 3 wk to an adequate palpable volume for biodistribution, SPECT imaging, and therapy studies. Animal conditions, including weight and tumor size, were monitored before initiating any in vivo studies. Animal studies were conducted in accordance with guidelines by the Canadian Council on Animal Care under protocol A20-0132 approved by the University of British Columbia Animal Care Committee.</p></div><div id="sec-4" class="subsection"><h3>SPECT Imaging Acquisition, Reconstruction, and Analysis</h3><p id="p-10">Pharmacokinetics were assessed with in vivo SPECT imaging (VECTor SPECT/CT; MILabs). One mouse was administered 1.84 ± 0.16 MBq of [<sup>226</sup>Ac]Ac-crown-TATE for SPECT, as described by Koniar et al. (<a id="xref-ref-12-3" class="xref-bibr" href="#ref-12">12</a>). Full descriptions of the SPECT imaging acquisition, reconstruction, and analysis procedures are presented in the supplemental materials (<a id="xref-ref-12-4" class="xref-bibr" href="#ref-12">12</a>,<a id="xref-ref-13-2" class="xref-bibr" href="#ref-13">13</a>,<a id="xref-ref-26-1" class="xref-bibr" href="#ref-26">26</a>).</p></div><div id="sec-5" class="subsection"><h3>Biodistribution Experiments</h3><p id="p-11">The ex vivo biodistribution was assessed in mice (<em>n</em> = 20) injected with [<sup>226</sup>Ac]Ac-crown-TATE (58.6 ± 1.6 kBq, 0.1198 ± 0.0032 nmol, 98.1 ± 2.6 μL) in the tumor and organs of interest. Mice were euthanized at 1, 3, 5, 24, and 48 h after injection. Full descriptions of ex vivo organ collection and activity quantifications are presented in the supplemental materials (<a id="xref-ref-27-1" class="xref-bibr" href="#ref-27">27</a>,<a id="xref-ref-28-1" class="xref-bibr" href="#ref-28">28</a>).</p></div><div id="sec-6" class="subsection"><h3>Radiation Dosimetry</h3><p id="p-12">Radiation dosimetry is necessary when considering future applications of <sup>226</sup>Ac given the decay properties of its progeny <sup>226</sup>Th, which emits 4 α-particles through very short-lived radionuclides. Preclinical radiation dosimetry in the tumor and organs of interest was computed following the MIRD formalism (<a id="xref-ref-29-1" class="xref-bibr" href="#ref-29">29</a>). A full description for assessing absorbed dose coefficients is presented in the supplemental materials (<a id="xref-ref-30-1" class="xref-bibr" href="#ref-30">30</a>–<a id="xref-ref-34-1" class="xref-bibr" href="#ref-34">34</a>).</p></div><div id="sec-7" class="subsection"><h3>Therapeutic Efficacy</h3><p id="p-13">To evaluate the therapeutic efficacy of [<sup>226</sup>Ac]Ac-crown-TATE, we assessed 3 levels of injected activity (125, 250, and 275 kBq) to observe its tumor control and toxicities compared with untreated control groups. The mice (<em>n</em> = 46) were placed into 5 groups such that all groups had similar variance in initial tumor size (133 ± 164 mm<sup>3</sup>). Mice remained in existing cages with their litter mates for adequate socialization throughout the study duration and were randomly assigned to a control or treatment protocol. A full description of the group stratification and treatment protocols is presented in the supplemental materials.</p><p id="p-14">The mice were monitored for changes in tumor volume and body weight for up to 60 d or until an experimental endpoint was reached, including tumor volume exceeding 1,000 mm<sup>3</sup> or weight loss greater than 20%. When an endpoint was reached, the mice were euthanized by an isoflurane overdose and CO<sub>2</sub> asphyxiation. Full descriptions of monitoring procedures and experimental endpoints are presented in the supplemental materials.</p></div><div id="sec-8" class="subsection"><h3>Statistical Analysis</h3><p id="p-15">All reported uncertainties correspond to 1 SD. Statistical analysis of the therapy study was completed with a Kaplan–Meier plot and log-rank test using the Survival Analysis package in Python (<a id="xref-ref-35-1" class="xref-bibr" href="#ref-35">35</a>). Statistical significance was set as a <em>P</em> value of less than 0.05.</p></div></div><div class="section results" id="sec-9"><h2 class="">RESULTS</h2><div id="sec-10" class="subsection"><h3>Quantitative SPECT Imaging</h3><p id="p-16">Quantitative SPECT images of an NRG mouse bearing an AR42J tumor injected with 1.84 ± 0.16 MBq of [<sup>226</sup>Ac]Ac-crown-TATE are presented in <a id="xref-fig-3-1" class="xref-fig" href="#F3">Figure 2</a>. SPECT images acquired 2.5 h after injection demonstrated high uptake in the tumor, kidneys, and bladder. Activity quantifications from the SPECT image exhibited strong agreement with ex vivo biodistribution data acquired after the final scan (<a id="xref-table-wrap-1-1" class="xref-table" href="#T1">Table 1</a>).</p><div id="F3" class="fig pos-float odd"><div class="highwire-figure"><div class="fig-inline-img-wrapper"><div class="fig-inline-img"><a href="https://jnm.snmjournals.org/content/jnumed/65/11/1762/F3.large.jpg?width=800&height=600&carousel=1" title="Quantitative SPECT/CT maximum-intensity projection of NRG mouse with AR42J tumor xenograft injected with [226Ac]Ac-crown-TATE and scanned 2.5 h after injection. A 2-mm gaussian filter was applied after reconstruction." class="highwire-fragment fragment-images colorbox-load" rel="gallery-fragment-images-596830861" data-figure-caption="<div class="highwire-markup"><div xmlns="http://www.w3.org/1999/xhtml">Quantitative SPECT/CT maximum-intensity projection of NRG mouse with AR42J tumor xenograft injected with [<sup>226</sup>Ac]Ac-crown-TATE and scanned 2.5 h after injection. A 2-mm gaussian filter was applied after reconstruction.</div></div>" data-icon-position="" data-hide-link-title="0"><span class="hw-responsive-img"><img class="highwire-fragment fragment-image lazyload" alt="FIGURE 2." src="data:image/gif;base64,R0lGODlhAQABAIAAAAAAAP///yH5BAEAAAAALAAAAAABAAEAAAIBRAA7" data-src="https://jnm.snmjournals.org/content/jnumed/65/11/1762/F3.medium.gif" width="414" height="440"/><noscript><img class="highwire-fragment fragment-image" alt="FIGURE 2." src="https://jnm.snmjournals.org/content/jnumed/65/11/1762/F3.medium.gif" width="414" height="440"/></noscript></span></a></div></div><ul class="highwire-figure-links inline"><li class="download-fig first"><a href="https://jnm.snmjournals.org/content/jnumed/65/11/1762/F3.large.jpg?download=true" class="highwire-figure-link highwire-figure-link-download" title="Download FIGURE 2." data-icon-position="" data-hide-link-title="0">Download figure</a></li><li class="new-tab"><a href="https://jnm.snmjournals.org/content/jnumed/65/11/1762/F3.large.jpg" class="highwire-figure-link highwire-figure-link-newtab" target="_blank" data-icon-position="" data-hide-link-title="0">Open in new tab</a></li><li class="download-ppt last"><a href="/highwire/powerpoint/124226" class="highwire-figure-link highwire-figure-link-ppt" data-icon-position="" data-hide-link-title="0">Download powerpoint</a></li></ul></div><div class="fig-caption"><span class="fig-label">FIGURE 2.</span> <p id="p-17" class="first-child">Quantitative SPECT/CT maximum-intensity projection of NRG mouse with AR42J tumor xenograft injected with [<sup>226</sup>Ac]Ac-crown-TATE and scanned 2.5 h after injection. A 2-mm gaussian filter was applied after reconstruction.</p><div class="sb-div caption-clear"></div></div></div><div id="T1" class="table pos-float"><div class="table-inline table-callout-links"><div class="callout"><span>View this table:</span><ul class="callout-links"><li class="view-inline first"><a href="" class="table-expand-inline" data-table-url="/highwire/markup/124359/expansion?postprocessors=highwire_tables%2Chighwire_reclass%2Chighwire_figures%2Chighwire_math%2Chighwire_inline_linked_media%2Chighwire_embed&table-expand-inline=1" data-icon-position="" data-hide-link-title="0">View inline</a></li><li class="view-popup last"><a href="/highwire/markup/124359/expansion?width=1000&height=500&iframe=true&postprocessors=highwire_tables%2Chighwire_reclass%2Chighwire_figures%2Chighwire_math%2Chighwire_inline_linked_media%2Chighwire_embed" class="colorbox colorbox-load table-expand-popup" rel="gallery-fragment-tables" data-icon-position="" data-hide-link-title="0">View popup</a></li></ul></div></div><div class="table-caption"><span class="table-label">TABLE 1.</span> <p id="p-18" class="first-child">Decay-Corrected %IA/g for Organs of Interest Determined by Activity Measurements from In Vivo SPECT Images and Ex Vivo Biodistribution Collected Immediately After Imaging</p><div class="sb-div caption-clear"></div></div></div></div><div id="sec-11" class="subsection"><h3>Biodistribution Studies</h3><p id="p-19">Ex vivo biodistribution data from mice injected with [<sup>226</sup>Ac]Ac-crown-TATE are presented in <a id="xref-fig-4-1" class="xref-fig" href="#F4">Figure 3</a>. [<sup>226</sup>Ac]Ac-crown-TATE demonstrated high uptake in the tumor, peaking at 5 h after injection (33.1 ± 7.1%IA/g with suitable retention at 48 h after injection (19.7 ± 2.6%IA/g). Of the organs collected, the kidneys, pancreas, stomach, and lungs showed uptake in the first 5 h after injection; however, clearance of the radiopharmaceutical by 24–48 h after injection was demonstrated. These results were expected because of the normal expression levels of SSTRs on these organs. The liver initially showed clearance in the first 5 h after injection but then showed sustained retention beyond 24 h. This ingrowth could indicate the presence of free [<sup>226</sup>Ac]Ac<sup>3+</sup>, which is known to accumulate in the liver (<a id="xref-ref-13-3" class="xref-bibr" href="#ref-13">13</a>,<a id="xref-ref-36-1" class="xref-bibr" href="#ref-36">36</a>). The remaining nontargeted organs demonstrated lower uptake (<5%IA/g) and good clearance by 48 h after injection.</p><div id="F4" class="fig pos-float odd"><div class="highwire-figure"><div class="fig-inline-img-wrapper"><div class="fig-inline-img"><a href="https://jnm.snmjournals.org/content/jnumed/65/11/1762/F4.large.jpg?width=800&height=600&carousel=1" title="Biodistribution of [226Ac]Ac-crown-TATE in NRG mice with AR42J tumors at 1, 3, 5, 24, and 48 h after injection." class="highwire-fragment fragment-images colorbox-load" rel="gallery-fragment-images-596830861" data-figure-caption="<div class="highwire-markup"><div xmlns="http://www.w3.org/1999/xhtml">Biodistribution of [<sup>226</sup>Ac]Ac-crown-TATE in NRG mice with AR42J tumors at 1, 3, 5, 24, and 48 h after injection.</div></div>" data-icon-position="" data-hide-link-title="0"><span class="hw-responsive-img"><img class="highwire-fragment fragment-image lazyload" alt="FIGURE 3." src="data:image/gif;base64,R0lGODlhAQABAIAAAAAAAP///yH5BAEAAAAALAAAAAABAAEAAAIBRAA7" data-src="https://jnm.snmjournals.org/content/jnumed/65/11/1762/F4.medium.gif" width="440" height="264"/><noscript><img class="highwire-fragment fragment-image" alt="FIGURE 3." src="https://jnm.snmjournals.org/content/jnumed/65/11/1762/F4.medium.gif" width="440" height="264"/></noscript></span></a></div></div><ul class="highwire-figure-links inline"><li class="download-fig first"><a href="https://jnm.snmjournals.org/content/jnumed/65/11/1762/F4.large.jpg?download=true" class="highwire-figure-link highwire-figure-link-download" title="Download FIGURE 3." data-icon-position="" data-hide-link-title="0">Download figure</a></li><li class="new-tab"><a href="https://jnm.snmjournals.org/content/jnumed/65/11/1762/F4.large.jpg" class="highwire-figure-link highwire-figure-link-newtab" target="_blank" data-icon-position="" data-hide-link-title="0">Open in new tab</a></li><li class="download-ppt last"><a href="/highwire/powerpoint/124228" class="highwire-figure-link highwire-figure-link-ppt" data-icon-position="" data-hide-link-title="0">Download powerpoint</a></li></ul></div><div class="fig-caption"><span class="fig-label">FIGURE 3.</span> <p id="p-20" class="first-child">Biodistribution of [<sup>226</sup>Ac]Ac-crown-TATE in NRG mice with AR42J tumors at 1, 3, 5, 24, and 48 h after injection.</p><div class="sb-div caption-clear"></div></div></div></div><div id="sec-12" class="subsection"><h3>Radiation Dosimetry</h3><p id="p-21">Ex vivo biodistribution data were used to estimate the preclinical radiation dosimetry for the tumor and various organs of interest in the animal model (<a id="xref-table-wrap-2-1" class="xref-table" href="#T2">Table 2</a>). For the tumor, kidneys, adrenal glands, pancreas, lungs, and stomach, the biexponential model was more appropriate for describing the radiopharmaceutical’s uptake and clearance patterns. However, for the blood, gallbladder, and small and large intestines, the monoexponential model provided an adequate fit. For all organs with an adequate fit (<em>R</em><sup>2</sup> > 0), the monoexponential and biexponential models are presented in <a id="xref-fig-5-1" class="xref-fig" href="#F5">Figure 4</a>. Complete model fitting results with all parameters are presented in Supplemental Table 3.</p><div id="T2" class="table pos-float"><div class="table-inline table-callout-links"><div class="callout"><span>View this table:</span><ul class="callout-links"><li class="view-inline first"><a href="" class="table-expand-inline" data-table-url="/highwire/markup/124186/expansion?postprocessors=highwire_tables%2Chighwire_reclass%2Chighwire_figures%2Chighwire_math%2Chighwire_inline_linked_media%2Chighwire_embed&table-expand-inline=1" data-icon-position="" data-hide-link-title="0">View inline</a></li><li class="view-popup last"><a href="/highwire/markup/124186/expansion?width=1000&height=500&iframe=true&postprocessors=highwire_tables%2Chighwire_reclass%2Chighwire_figures%2Chighwire_math%2Chighwire_inline_linked_media%2Chighwire_embed" class="colorbox colorbox-load table-expand-popup" rel="gallery-fragment-tables" data-icon-position="" data-hide-link-title="0">View popup</a></li></ul></div></div><div class="table-caption"><span class="table-label">TABLE 2.</span> <p id="p-22" class="first-child">Summary of Radiation Dosimetry Estimates with Best-Fit Model and Correlation Coefficient (<em>R</em><sup>2</sup>), Time Integrated Activity Coefficient (<span class="inline-formula" id="inline-formula-1"><span class="highwire-responsive-lazyload"><img src="data:image/gif;base64,R0lGODlhAQABAIAAAAAAAP///yH5BAEAAAAALAAAAAABAAEAAAIBRAA7" class="highwire-embed lazyload" alt="Embedded Image" data-src="https://jnm.snmjournals.org/sites/default/files/highwire/jnumed/65/11/1762/T2/embed/mml-math-1.gif"/><noscript><img class="highwire-embed" alt="Embedded Image" src="https://jnm.snmjournals.org/sites/default/files/highwire/jnumed/65/11/1762/T2/embed/mml-math-1.gif"/></noscript></span></span>), Absorbed Dose Per Decay (<em>S</em>), and Absorbed Dose Coefficients (<em>D</em>)</p><div class="sb-div caption-clear"></div></div></div><div id="F5" class="fig pos-float odd"><div class="highwire-figure"><div class="fig-inline-img-wrapper"><div class="fig-inline-img"><a href="https://jnm.snmjournals.org/content/jnumed/65/11/1762/F5.large.jpg?width=800&height=600&carousel=1" title="Ex vivo biodistribution activity data fit with monoexponential (red) and biexponential (green) decay models. Only organs with fits with R2 > 0 are presented." class="highwire-fragment fragment-images colorbox-load" rel="gallery-fragment-images-596830861" data-figure-caption="<div class="highwire-markup"><div xmlns="http://www.w3.org/1999/xhtml">Ex vivo biodistribution activity data fit with monoexponential (red) and biexponential (green) decay models. Only organs with fits with <em>R</em><sup>2</sup> > 0 are presented.</div></div>" data-icon-position="" data-hide-link-title="0"><span class="hw-responsive-img"><img class="highwire-fragment fragment-image lazyload" alt="FIGURE 4." src="data:image/gif;base64,R0lGODlhAQABAIAAAAAAAP///yH5BAEAAAAALAAAAAABAAEAAAIBRAA7" data-src="https://jnm.snmjournals.org/content/jnumed/65/11/1762/F5.medium.gif" width="251" height="440"/><noscript><img class="highwire-fragment fragment-image" alt="FIGURE 4." src="https://jnm.snmjournals.org/content/jnumed/65/11/1762/F5.medium.gif" width="251" height="440"/></noscript></span></a></div></div><ul class="highwire-figure-links inline"><li class="download-fig first"><a href="https://jnm.snmjournals.org/content/jnumed/65/11/1762/F5.large.jpg?download=true" class="highwire-figure-link highwire-figure-link-download" title="Download FIGURE 4." data-icon-position="" data-hide-link-title="0">Download figure</a></li><li class="new-tab"><a href="https://jnm.snmjournals.org/content/jnumed/65/11/1762/F5.large.jpg" class="highwire-figure-link highwire-figure-link-newtab" target="_blank" data-icon-position="" data-hide-link-title="0">Open in new tab</a></li><li class="download-ppt last"><a href="/highwire/powerpoint/124259" class="highwire-figure-link highwire-figure-link-ppt" data-icon-position="" data-hide-link-title="0">Download powerpoint</a></li></ul></div><div class="fig-caption"><span class="fig-label">FIGURE 4.</span> <p id="p-23" class="first-child">Ex vivo biodistribution activity data fit with monoexponential (red) and biexponential (green) decay models. Only organs with fits with <em>R</em><sup>2</sup> > 0 are presented.</p><div class="sb-div caption-clear"></div></div></div><p id="p-24">The tumor demonstrated the highest absorbed dose coefficient (222.3 mGy/kBq), and all other reported organs were less than 80 mGy/kBq. The highest dose coefficients for normal organs were the stomach, kidneys, and pancreas. These organs will be of interest in future studies investigating the maximum tolerated dose. Dosimetry estimates in the blood were especially low (0.38 mGy/kBq), with a tumor-to-blood dose ratio of 590:1, suggesting a lower risk of hematologic toxicities.</p><p id="p-25">Dosimetry estimates from activity measurements in the bone, muscle, liver, bladder, spleen, brain, and heart were excluded because of poor fitting (<em>R</em><sup>2</sup> < 0) with both models. Of the excluded organs of interest, the bone, muscle, spleen, brain, and heart had very low radiopharmaceutical uptake and are unlikely be dose-limiting organs in future applications. Modeling for the bladder was insufficient because of large interanimal variability; however, the bladder demonstrated good clearance (<5%IA/g) within 5 h after injection and thus is unlikely to be a dose-limiting organ. The liver was also excluded because of poor fitting as it showed an increasing activity accumulation beyond 5 h after injection, which may be a result of free [<sup>226</sup>Ac]Ac<sup>3+</sup> activity circulating (<a id="xref-ref-13-4" class="xref-bibr" href="#ref-13">13</a>,<a id="xref-ref-36-2" class="xref-bibr" href="#ref-36">36</a>). Dosimetry estimates in the liver require more complex modeling to achieve better accuracy. Because of the observed pharmacokinetics, the liver could be a dose-limiting organ, but further investigation is required.</p></div><div id="sec-13" class="subsection"><h3>Therapy Monitoring</h3><p id="p-26">The survival outcomes from the therapy monitoring study are presented in a Kaplan–Meier plot (<a id="xref-fig-6-1" class="xref-fig" href="#F6">Fig. 5</a>). All pairwise log-rank tests between control and treatment groups are presented in Supplemental Table 4. Median survival after [<sup>226</sup>Ac]Ac-crown-TATE injection was 16, 24, and 27 d for the 125, 250, and 375 kBq treatment groups, respectively. However, for both the saline and the crown-TATE control groups, median survival after injection was 7 d. Additionally, there was no statistically significant difference (<em>P</em> = 0.39) in survival probability between the saline and nonradioactive crown-TATE control groups, indicating that the unlabeled chelator-peptide does not induce an independent therapeutic effect. All treatment groups demonstrated statistically significant differences (<em>P</em> < 0.005) in survival probability when compared to both control groups. The groups treated with a medium (250 kBq) and high (375 kBq) injected activity had statistically significant differences in survival probability from the group treated with a low injected activity (125 kBq) (<em>P</em> < 0.005), indicating that the higher injected activities prolonged survival. However, the medium and high groups did not show statistically significant differences (<em>P</em> = 0.51) in survival probability. Further optimization of injected activity is required to determine the injected activity that maximizes tumor control and improves survival probability.</p><div id="F6" class="fig pos-float odd"><div class="highwire-figure"><div class="fig-inline-img-wrapper"><div class="fig-inline-img"><a href="https://jnm.snmjournals.org/content/jnumed/65/11/1762/F6.large.jpg?width=800&height=600&carousel=1" title="Kaplan–Meier plot of survival probability in NRG mice with AR42J tumors after treatment with saline; nonradioactive crown-TATE; and 125, 250, or 375 kBq of [226Ac]Ac-crown-TATE." class="highwire-fragment fragment-images colorbox-load" rel="gallery-fragment-images-596830861" data-figure-caption="<div class="highwire-markup"><div xmlns="http://www.w3.org/1999/xhtml">Kaplan–Meier plot of survival probability in NRG mice with AR42J tumors after treatment with saline; nonradioactive crown-TATE; and 125, 250, or 375 kBq of [<sup>226</sup>Ac]Ac-crown-TATE.</div></div>" data-icon-position="" data-hide-link-title="0"><span class="hw-responsive-img"><img class="highwire-fragment fragment-image lazyload" alt="FIGURE 5." src="data:image/gif;base64,R0lGODlhAQABAIAAAAAAAP///yH5BAEAAAAALAAAAAABAAEAAAIBRAA7" data-src="https://jnm.snmjournals.org/content/jnumed/65/11/1762/F6.medium.gif" width="440" height="224"/><noscript><img class="highwire-fragment fragment-image" alt="FIGURE 5." src="https://jnm.snmjournals.org/content/jnumed/65/11/1762/F6.medium.gif" width="440" height="224"/></noscript></span></a></div></div><ul class="highwire-figure-links inline"><li class="download-fig first"><a href="https://jnm.snmjournals.org/content/jnumed/65/11/1762/F6.large.jpg?download=true" class="highwire-figure-link highwire-figure-link-download" title="Download FIGURE 5." data-icon-position="" data-hide-link-title="0">Download figure</a></li><li class="new-tab"><a href="https://jnm.snmjournals.org/content/jnumed/65/11/1762/F6.large.jpg" class="highwire-figure-link highwire-figure-link-newtab" target="_blank" data-icon-position="" data-hide-link-title="0">Open in new tab</a></li><li class="download-ppt last"><a href="/highwire/powerpoint/124334" class="highwire-figure-link highwire-figure-link-ppt" data-icon-position="" data-hide-link-title="0">Download powerpoint</a></li></ul></div><div class="fig-caption"><span class="fig-label">FIGURE 5.</span> <p id="p-27" class="first-child">Kaplan–Meier plot of survival probability in NRG mice with AR42J tumors after treatment with saline; nonradioactive crown-TATE; and 125, 250, or 375 kBq of [<sup>226</sup>Ac]Ac-crown-TATE.</p><div class="sb-div caption-clear"></div></div></div><p id="p-28"><a id="xref-fig-7-1" class="xref-fig" href="#F7">Figure 6</a> presents the mean tumor volume and mean percentage net weight loss for all control and treatment groups. Tumor volume and net weight loss for individual mice in all treatment groups are available in Supplemental Figure 3. [<sup>226</sup>Ac]Ac-crown-TATE treatments were effective at prolonging survival in tumor-bearing mice by slowing tumor growth. The rate of tumor growth was moderately slowed in the low-injected-activity (125 kBq) treatment group. Treatment with the medium injected activity (250 kBq) and high injected activity (375 kBq) showed the best control of tumor growth rates and had similar effects on mean tumor volume over time. Overall, the treatment was well tolerated at all levels of injected activity, with no noted toxicity side effects. All mice in the therapy monitoring study reached the experimental endpoint because of a large tumor volume (>1,000 mm<sup>3</sup>), and no animals experienced any weight loss of concern. Future studies will examine dose escalation to determine the maximum tolerated dose and further investigate the dose-dependent biologic response.</p><div id="F7" class="fig pos-float odd"><div class="highwire-figure"><div class="fig-inline-img-wrapper"><div class="fig-inline-img"><a href="https://jnm.snmjournals.org/content/jnumed/65/11/1762/F7.large.jpg?width=800&height=600&carousel=1" title="Mean tumor volume (top) and mean percentage weight loss (bottom) as metrics of therapeutic response in NRG mice with AR42J tumors after treatment with saline; nonradioactive crown-TATE; and 125, 250, or 375 kBq of [226Ac]Ac-crown-TATE. Error bars represent SD." class="highwire-fragment fragment-images colorbox-load" rel="gallery-fragment-images-596830861" data-figure-caption="<div class="highwire-markup"><div xmlns="http://www.w3.org/1999/xhtml">Mean tumor volume (top) and mean percentage weight loss (bottom) as metrics of therapeutic response in NRG mice with AR42J tumors after treatment with saline; nonradioactive crown-TATE; and 125, 250, or 375 kBq of [<sup>226</sup>Ac]Ac-crown-TATE. Error bars represent SD.</div></div>" data-icon-position="" data-hide-link-title="0"><span class="hw-responsive-img"><img class="highwire-fragment fragment-image lazyload" alt="FIGURE 6." src="data:image/gif;base64,R0lGODlhAQABAIAAAAAAAP///yH5BAEAAAAALAAAAAABAAEAAAIBRAA7" data-src="https://jnm.snmjournals.org/content/jnumed/65/11/1762/F7.medium.gif" width="440" height="381"/><noscript><img class="highwire-fragment fragment-image" alt="FIGURE 6." src="https://jnm.snmjournals.org/content/jnumed/65/11/1762/F7.medium.gif" width="440" height="381"/></noscript></span></a></div></div><ul class="highwire-figure-links inline"><li class="download-fig first"><a href="https://jnm.snmjournals.org/content/jnumed/65/11/1762/F7.large.jpg?download=true" class="highwire-figure-link highwire-figure-link-download" title="Download FIGURE 6." data-icon-position="" data-hide-link-title="0">Download figure</a></li><li class="new-tab"><a href="https://jnm.snmjournals.org/content/jnumed/65/11/1762/F7.large.jpg" class="highwire-figure-link highwire-figure-link-newtab" target="_blank" data-icon-position="" data-hide-link-title="0">Open in new tab</a></li><li class="download-ppt last"><a href="/highwire/powerpoint/124209" class="highwire-figure-link highwire-figure-link-ppt" data-icon-position="" data-hide-link-title="0">Download powerpoint</a></li></ul></div><div class="fig-caption"><span class="fig-label">FIGURE 6.</span> <p id="p-29" class="first-child">Mean tumor volume (top) and mean percentage weight loss (bottom) as metrics of therapeutic response in NRG mice with AR42J tumors after treatment with saline; nonradioactive crown-TATE; and 125, 250, or 375 kBq of [<sup>226</sup>Ac]Ac-crown-TATE. Error bars represent SD.</p><div class="sb-div caption-clear"></div></div></div></div></div><div class="section discussion" id="sec-14"><h2 class="">DISCUSSION</h2><p id="p-30">[<sup>226</sup>Ac]Ac-crown-TATE was evaluated for its potential as a theranostic agent in mice with AR42J tumor xenografts. SPECT imaging demonstrated a strong correlation with ex vivo measurements. Our comprehensive biodistribution study also supported the results seen in SPECT imaging, with high tumor uptake and retention. Nontargeted organs with demonstrated uptake included the kidneys, stomach, and pancreas. Radiation dosimetry confirmed that the tumor received the highest dose of all collected organs. Dosimetry estimates also indicated that the stomach, kidneys, and pancreas received the highest off-target dose. Further investigation is required to determine the maximum tolerated dose. The results of the therapy monitoring study demonstrated that <sup>226</sup>Ac can be leveraged for therapeutic effects by slowing tumor growth and significantly prolonging survival without toxicities relative to untreated control groups. Thus, we have demonstrated that [<sup>226</sup>Ac]Ac-crown-TATE has potential as a theranostic agent in this proof-of-concept study. On the basis of the outcomes of this study, there is value in continuing [<sup>226</sup>Ac]Ac-crown-TATE radiopharmaceutical development.</p><p id="p-31">For this study, <sup>226</sup>Ac was produced by the bombardment of a uranium carbide target with high-energy 480 MeV protons at TRIUMF’s Isotope Separation and Acceleration facility. Although this production method is ideal for producing activity levels sufficient for preclinical proof-of-feasibility studies with high radiochemical purity, it is not sufficient for large-scale clinical isotope production. However, one of the most promising large-scale <sup>225</sup>Ac production methods under investigation uses the <sup>226</sup>Ra(p,2n)<sup>225</sup>Ac nuclear reaction on medium-energy (proton energy ≤ 20 MeV) cyclotrons (<a id="xref-ref-37-1" class="xref-bibr" href="#ref-37">37</a>). At these energy levels, the <sup>226</sup>Ra(p,n)<sup>226</sup>Ac nuclear reaction maintains a significant cross-sectional yield (<a id="xref-ref-38-1" class="xref-bibr" href="#ref-38">38</a>). Understanding the imaging and therapeutic potential of <sup>226</sup>Ac in itself may help to facilitate the development of colabeled [<sup>225/226</sup>Ac]Ac-radiopharmaceuticals in the future while also enabling earlier distribution and use of <sup>225/226</sup>Ac produced via <sup>226</sup>Ra(p,x) routes. Alternative isotopically pure <sup>226</sup>Ac production routes require further investigation.</p><p id="p-32">Although this therapy study demonstrated the antitumor capabilities of <sup>226</sup>Ac, no animals achieved a complete response. Because there were no off-target toxicities seen in the mice injected with [<sup>226</sup>Ac]Ac-crown-TATE, we believe the injected activity levels can be further optimized. Multicycle fractionated regimens could be leveraged to deliver higher doses to cancer cells while permitting normal-tissue repair (<a id="xref-ref-39-1" class="xref-bibr" href="#ref-39">39</a>). We also observed a trend between initial tumor volume and therapeutic response in terms of slowed tumor growth and overall survival extension (Supplemental Fig. 3). Further investigation is required to determine the relationship between initial tumor burden and therapeutic outcome with treatment groups stratified by tumor volume at the time of initial treatment.</p><p id="p-33">There are potential risks to the clinical implementation of <sup>226</sup>Ac, which requires dose-escalation studies to determine the maximum tolerated dose and organs at risk to dose-limiting toxicities. In particular, the liver demonstrated indications of free-activity uptake and may cause unexpected toxicities when scaling up to the clinic. However, to reduce undesirable radiation exposure, several chelators have shown effective whole-body clearance of free <sup>225</sup>Ac and could also be successful in clearing free <sup>226</sup>Ac (<a id="xref-ref-40-1" class="xref-bibr" href="#ref-40">40</a>). Additionally, <sup>226</sup>Ra (t<sub>1/2</sub> = 1,600 y) exposure could present a potential hazard to patients; however, a therapeutic dose of 10 MBq of <sup>226</sup>Ac results in less than 4 Bq of <sup>226</sup>Ra, which is unlikely to cause secondary bone sarcomas (<a id="xref-ref-41-1" class="xref-bibr" href="#ref-41">41</a>).</p><p id="p-34">To the best of our knowledge, this study is the first of its kind to demonstrate the therapeutic potency of <sup>226</sup>Th and its α-emissions. The proposed <sup>226</sup>Ac/<sup>226</sup>Th in vivo generator is similar in physical characteristics to the <sup>212</sup>Pb/<sup>212</sup>Bi in vivo generator used for α-emitter radiopharmaceutical therapy (<a id="xref-ref-42-1" class="xref-bibr" href="#ref-42">42</a>). In both cases, the parent radionuclide undergoes β<sup>−</sup>-decay to an α-emitting daughter, <sup>226</sup>Th or <sup>212</sup>Bi. Because of the large mass of the daughter nuclei relative to the β<sup>−</sup>-particle, nuclear recoil from the chelator complex is largely negligible (<a id="xref-ref-43-1" class="xref-bibr" href="#ref-43">43</a>). Some radiolytic degradation of the chelator is thought to be caused by Auger and conversion electrons, of which <sup>226</sup>Ac has lower yields than <sup>212</sup>Pb (<a id="xref-ref-44-1" class="xref-bibr" href="#ref-44">44</a>,<a id="xref-ref-45-1" class="xref-bibr" href="#ref-45">45</a>). Additionally, the α-emitter <sup>226</sup>Th (t<sub>½</sub> = 30.6 min) has a shorter half-life than <sup>212</sup>Bi (t<sub>½</sub> = 61 min), which lessens the likelihood for in vivo redistribution from targeted sites (<a id="xref-ref-46-1" class="xref-bibr" href="#ref-46">46</a>). Thus, it can be concluded that <sup>226</sup>Ac/<sup>226</sup>Th may have optimal physical properties to act as an in vivo generator of α-emissions. Further investigation is required to quantitatively estimate <sup>226</sup>Th release from <sup>226</sup>Ac-labeled radiopharmaceuticals. Additionally, because of the shorter physical half-life of <sup>226</sup>Ac relative to <sup>225</sup>Ac, small-molecule targeting moieties with rapid circulation and a shorter residence time may have strong therapeutic potential for radiopharmaceutical therapy with α-emitters (<a id="xref-ref-47-1" class="xref-bibr" href="#ref-47">47</a>).</p><p id="p-35">Overall, we demonstrated that there is potential for <sup>226</sup>Ac to act as a standalone theranostic radionuclide through SPECT imaging and radiopharmaceutical therapy with α-emitters. Future investigations with <sup>226</sup>Ac-labeled radiopharmaceuticals will benefit from the framework established in this study.</p></div><div class="section conclusion" id="sec-15"><h2 class="">CONCLUSION</h2><p id="p-36">We have presented the feasibility and capability of applying <sup>226</sup>Ac as standalone theranostic radioisotope with the preclinical radiopharmaceutical [<sup>226</sup>Ac]Ac-crown-TATE in a murine model with a neuroendocrine tumor burden. Quantitative SPECT imaging was achieved with a strong correlation to ex vivo activity measurements. Dosimetry estimates indicated that the tumor received the highest dose per unit injected activity. Therapy studies indicated that <sup>226</sup>Ac prolonged median survival by slowing tumor growth, as compared with control groups, without inducing observable side effects or toxicities. Future studies are required to ascertain the maximum tolerated dose and potential toxicities of this radiopharmaceutical. Overall, it has been demonstrated that <sup>226</sup>Ac can serve dual roles as a diagnostic and therapeutic radioisotope. This work proposes that <sup>226</sup>Ac can benefit preclinical radiopharmaceutical development and perhaps facilitate personalized patient treatment delivery in the future.</p></div><div class="section" id="sec-16"><h2 class="">DISCLOSURE</h2><p id="p-37">This study was financially supported by the following NSERC (National Science and Engineering Research Council of Canada) Discovery Grants: RGPIN-2022-03887 (Hua Yang), SAPIN-2021-00030 (Peter Kunz), RGPIN-2021-04093 (Paul Schaffer), and RGPIN-2018-04997 (Valery Radchenko). Additionally, funding was obtained through Canada Foundation for Innovation (CFI) project 25413 (Cristina Rodríguez-Rodríguez) and the Government of Canada’s New Frontiers in Research Fund–Exploration (NFRFE-2019-00128, Peter Kunz). TRIUMF receives federal funding via a contribution agreement with the NRC (National Research Council of Canada). Luke Wharton, Hua Yang, and Paul Schaffer have pending patent rights to the crown chelator. No other potential conflict of interest relevant to this article was reported.</p></div><div class="section" id="sec-17"><div class="boxed-text" id="boxed-text-1"><div class="section" id="sec-18"><h4>KEY POINTS</h4><p id="p-38"><strong>QUESTION:</strong> Can <sup>226</sup>Ac act as an independent theranostic agent through SPECT imaging and targeted α-therapy?</p><p id="p-39"><strong>PERTINENT FINDINGS:</strong> [<sup>226</sup>Ac]Ac-crown-TATE demonstrated both diagnostic and therapeutic capabilities in mice bearing neuroendocrine tumors.</p><p id="p-40"><strong>IMPLICATIONS FOR PATIENT CARE:</strong> Demonstrating the diagnostic and therapeutic applications for <sup>226</sup>Ac can help facilitate preclinical <sup>225</sup>Ac-radiopharmaceutical development to translate novel treatments to clinical settings more efficiently.</p></div></div></div><div class="section fn-group" id="fn-group-1"><h2>Footnotes</h2><ul><li class="fn" id="fn-1"><p id="p-1">Published online Oct. 3, 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class="received-label">Received for publication </span>May 2, 2024.</li><li xmlns:hwp="http://schema.highwire.org/Journal" class="accepted" hwp:start="2024-09-09"><span class="accepted-label">Accepted for publication </span>September 9, 2024.</li></ul><span class="highwire-journal-article-marker-end"></span></div><span class="related-urls"></span></div></div> </div> </div> </div> </div> </div> </div></div> </div> </div> <div class="panel-separator"></div><div class="panel-pane pane-highwire-node-pager" > <div class="pane-content"> <div class="pager highwire-pager pager-mini clearfix highwire-node-pager highwire-article-pager"><span class="pager-prev"><a href="/content/65/11/1754" title="Routine Use of [64Cu]Cu-DOTATATE PET/CT in a Neuroendocrine Tumor Center: Referral Patterns and Image Results of 2,249 Consecutive Scans" rel="prev" class="pager-link-prev link-icon"><span class="icon-circle-arrow-left"></span> <span class="title">Previous</span></a></span><span class="pager-next"><a 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