Nuclear medicine and biology最新文献

{"title":"[¹⁸F]BCPP-EF positron emission tomography of rat ovaries for evaluation of mitochondrial function.","authors":"Yuki Tomonari, Hiroyuki Ohba, Hideo Tsukada","doi":"10.1016/j.nucmedbio.2025.108996","DOIUrl":"https://doi.org/10.1016/j.nucmedbio.2025.108996","url":null,"abstract":"<p><strong>Background: </strong>The ovary is an important female organ not only for pregnancy but also for the regulation of life activities via hormone release. Ovarian function is measured by blood hormone levels, but the hormone level reflects only the ovarian reserve and no other essential ovarian functions, such as nurturing and expelling follicles. Ovarian fibrosis is related to essential ovarian function; however, the existing methods for evaluating fibrosis are invasive. Ovarian fibrosis has been reported to be associated with mitochondrial function. We hypothesized that positron emission tomography (PET) imaging of mitochondria could be a new, non-invasive method for evaluating essential ovarian function. In this study, we investigated the age-related changes in ovarian fibrosis using the mitochondrial complex-I (MC-I) PET probe, 2-tert-butyl-4-chloro-5-{6-[2-(2-¹⁸F-fluoroethoxy)-ethoxy]-pyridin-3-ylmethoxy}-2H-pyridazin-3-one ([¹⁸F]BCPP-EF).</p><p><strong>Results: </strong>Aged rats, whose ovary function decline, exhibited a higher uptake of [¹⁸F]BCPP-EF in the ovary than young rats, and this high uptake in aged rats was suppressed by mitoquinone, a superoxide scavenger. Increased [¹⁸F]BCPP-EF uptake in the ovary was associated with ovarian fibrosis, but not with AMH level which reflects the ovarian reserve. Furthermore, the measurement of MC protein levels showed that the protein levels of MC-I increased with age, whereas those of MC-V decreased.</p><p><strong>Conclusions: </strong>This study demonstrated that [¹⁸F]BCPP-EF can detect age-related changes in essential ovarian function evaluated by ovarian fibrosis. Therefore, [¹⁸F]BCPP-EF-PET is a useful non-invasive method for evaluating essential ovarian functions and will contribute to basic research on ovarian aging as well as drug discovery targeting ovarian dysfunction.</p>","PeriodicalId":19363,"journal":{"name":"Nuclear medicine and biology","volume":"142-143 ","pages":"108996"},"PeriodicalIF":3.6,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143040129","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cross sections of the ²²⁶Ra(p,xn) reactions relevant for ²²⁵Ac production.","authors":"Ondřej Lebeda, Kateřina Ondrák Fialová, Lukáš Ondrák, Jaroslav Červenák, Jan Ráliš, Jan Štursa","doi":"10.1016/j.nucmedbio.2025.108995","DOIUrl":"https://doi.org/10.1016/j.nucmedbio.2025.108995","url":null,"abstract":"<p><p>Limited availability constrains the implementation of ²²⁵Ac, the most promising α emitter for targeted therapy, in clinical practice. Proton activation of ²²⁶Ra is one of few realistic solutions to this problem. We have therefore measured cross sections of relevant ²²⁶Ra(p,xn) nuclear reactions in the energy range of 12.0 to 17.2 MeV. The obtained results allowed us to deduce the yield of ²²⁴Ac, ²²⁵Ac, and ²²⁶Ac. The consequences of our data to predictions of production capacity and radionuclidic purity of ²²⁵Ac are thoroughly discussed, and their comparison with previous measurements and with the prediction of the TALYS 1.96 nuclear reaction model code run with default parameters are provided.</p>","PeriodicalId":19363,"journal":{"name":"Nuclear medicine and biology","volume":"142-143 ","pages":"108995"},"PeriodicalIF":3.6,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143029254","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterization of a novel PET radioligand for mitochondrial complex I in nonhuman primate.","authors":"Yulong Xu, Yiming Xu, Frederick Andrew Bagdasarian, Tewodros Mulugeta Dagnew, Hua Cheng, Yanli Wang, Yongle Wang, Leyi Kang, Hsiao-Ying Wey, Can Zhang, Shijun Zhang, Changning Wang","doi":"10.1016/j.nucmedbio.2025.108993","DOIUrl":"https://doi.org/10.1016/j.nucmedbio.2025.108993","url":null,"abstract":"<p><p>The role of mitochondrial complex I (MC-I) dysfunction is well-documented across a range of neurodegenerative disorders. Recently, a novel positron emission tomography (PET) radioligand, [¹⁸F]CNL02, has been synthesized to target MC-I. In this paper, we provide a comprehensive characterization of [¹⁸F]CNL02, using nonhuman primate as a model system. In the brain of a rhesus macaque, [¹⁸F]CNL02 demonstrated specific binding in regions expressing MC-I. All observed brain regions showed rapid kinetic profiles. Analysis of arterial plasma indicated a swift clearance of [¹⁸F]CNL02 from the bloodstream. Metabolite analysis identified two predominant radiometabolites in the plasma. The regional brain time-activity curves (TACs) for [¹⁸F]CNL02 were effectively characterized through a two-tissue compartment model (2TCM). Furthermore, the total distribution volume was reliably estimated employing the Logan plot method. Consequently, continued development and refinement of [¹⁸F]CNL02 are imperative.</p>","PeriodicalId":19363,"journal":{"name":"Nuclear medicine and biology","volume":"142-143 ","pages":"108993"},"PeriodicalIF":3.6,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143009022","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preclinical evaluation of ⁶⁸Ga-labeled folic acid conjugates for visualization of inflammatory foci.","authors":"Kristina A Petrosova, Aleksandr S Lunev, Marat G Rakhimov, Aleksey E Machulkin, Natalia S Volkova, Fedor I Vasilevich, Anton A Larenkov","doi":"10.1016/j.nucmedbio.2024.108991","DOIUrl":"https://doi.org/10.1016/j.nucmedbio.2024.108991","url":null,"abstract":"<p><strong>Introduction: </strong>Folate receptors (FR) have been considered a convenient target for different radiopharmaceuticals in recent years. Multifarious ⁶⁸Ga-labeled folate conjugates have been proposed as promising agents for the PET imaging of FR-overexpressing malignant neoplasms. In addition, radiolabeled folate-based conjugates can be effective for imaging non-tumor pathological foci characterized by a pronounced cluster of activated macrophages. We previously reported that a conjugate of folic acid with the NODAGA-chelator, labeled with gallium-68 and containing a (His-Glu)₂-tag ([⁶⁸Ga]Ga-NODAGA-[Lys-(HE)₂]-folic acid), is suitable for imaging tumor lesions characterized by an increased density of FR. Introduction of the (His-Glu)₂-tag into the structure of the folate radioconjugate significantly reduced its accumulation in non-target tissues (e.g., kidneys), leaving the accumulation in tumors at least at the same level, and even increasing it. The present study assessed the suitability of the developed molecule (in comparison with the unmodified analog) for imaging foci of non-oncological etiology characterized by a pronounced macrophage response.</p><p><strong>Methods: </strong>Systemic juvenile idiopathic arthritis (JIA), reproduced in Wistar rats, was used as the pathology model. Acute inflammatory processes of soft tissues of septic and aseptic etiologies were selected as differential models.</p><p><strong>Results: </strong>The results obtained in this study showed a significantly elevated level of accumulation in the JIA focus compared to healthy rat paws and accumulation in the foci of differential models of the inflammatory process, which confirms the macrophage-mediated pathway of accumulation of the studied compounds. Simultaneously, the ratio of accumulation in pathology to accumulation in comparable healthy tissues in all studied pathologies was significantly high.</p><p><strong>Conclusion: </strong>The data obtained allowed us to conclude the diagnostic potential of new radiolabeled folate-based conjugate with (His-Glu)₂-tag for pharmacokinetic property optimization in the radionuclide diagnosis of rheumatoid and other diseases characterized by a pronounced macrophage immune response. The mathematical compartment model quantitatively confirmed that the additional (His-Glu)₂ fragment introduced in the molecule acts in favor of potential radiopharmaceutical use to visualize inflammatory processes by positron emission tomography.</p>","PeriodicalId":19363,"journal":{"name":"Nuclear medicine and biology","volume":"142-143 ","pages":"108991"},"PeriodicalIF":3.6,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143009037","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Alpha Atlas: Mapping global production of α-emitting radionuclides for targeted alpha therapy.","authors":"Marianna Tosato, Chiara Favaretto, Janke Kleynhans, Andrew R Burgoyne, Jean-François Gestin, Nicholas P van der Meulen, Amirreza Jalilian, Ulli Köster, Mattia Asti, Valery Radchenko","doi":"10.1016/j.nucmedbio.2024.108990","DOIUrl":"https://doi.org/10.1016/j.nucmedbio.2024.108990","url":null,"abstract":"<p><p>Targeted Alpha Therapy has shown great promise in cancer treatment, sparking significant interest over recent decades. However, its broad adoption has been impeded by the scarcity of alpha-emitters and the complexities related to their use. The availability of these radionuclides is often constrained by the intricate production processes and purification, as well as regulatory and logistical challenges. Moreover, the high cost and technical difficulties associated with handling and applying alpha-emitting radionuclides pose additional barriers to their clinical implementation. This Alpha Atlas provides an in-depth overview of the leading alpha-particle emitting radionuclide candidates for clinical use, focusing on their production processes and supply chains. By mapping the current facilities that produce and supply these radionuclides, this atlas aims to assist researchers, clinicians, and industries in initiating or scaling up the applications of alpha-emitters. The Alpha Atlas aspires to act as a strategic guide, facilitating collaboration and driving forward the integration of these potent therapeutic agents into cancer treatment practices.</p>","PeriodicalId":19363,"journal":{"name":"Nuclear medicine and biology","volume":"142-143 ","pages":"108990"},"PeriodicalIF":3.6,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142984278","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Solid phase extraction chromatography-based radiochemical isolation of cyclotron-produced ⁵¹Mn from enriched ⁵⁴Fe targets.","authors":"Kendall E Barrett, Jason C Mixdorf, Johan Svedjehed, Jeanine Batterton, Jennifer Eagleburger, Yongjun Yan, Katherine Gagnon, Eduardo Aluicio-Sarduy, Todd E Barnhart, Jonathan W Engle","doi":"10.1016/j.nucmedbio.2024.108989","DOIUrl":"https://doi.org/10.1016/j.nucmedbio.2024.108989","url":null,"abstract":"<p><p>We report DGA extraction chromatography isolation of ⁵¹Mn from isotopically enriched ⁵⁴Fe. The method has been studied in semi-automated and automated realizations. The former achieves a decay corrected radiochemical yield of 78 ± 1 % (n = 3) and a separation factor of (1.0 ± 0.8) x 10⁵ (n = 3). With GE HealthCare's Solid Target Platform (STP) and FASTlab the latter, fully automated method achieves a decay corrected radiochemical yield of 87 ± 1 % (n = 3) and a separation factor of (2.7 ± 0.9) x 10⁴ (n = 3). Both setups efficiently isolate cyclotron-produced ⁵¹MnCl₂ suitable for human administration as determined by developed Chemistry, Manufacturing, and Controls (CMC) acceptance criteria, and support exploration of ⁵¹Mn as a clinical diagnostic tool.</p>","PeriodicalId":19363,"journal":{"name":"Nuclear medicine and biology","volume":"142-143 ","pages":"108989"},"PeriodicalIF":3.6,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142896327","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PET imaging of the anticancer drug candidate [¹¹C]trimebutine in a rat glioma model.","authors":"Jia-Zhe Lin, Maria Kominia, Janine Doorduin, Erik F J de Vries","doi":"10.1016/j.nucmedbio.2024.108985","DOIUrl":"https://doi.org/10.1016/j.nucmedbio.2024.108985","url":null,"abstract":"<p><strong>Purpose: </strong>Preclinical studies suggest that trimebutine could be a potential treatment for glioblastoma. The aim of this study was to investigate the distribution, kinetics and tumor accumulation of [¹¹C]trimebutine.</p><p><strong>Method: </strong>A proliferation assay and cell scratch healing assay were performed to confirm the antitumor effects of trimebutine on C6 glioma cells in-vitro. Trimebutine was subsequently labeled with ¹¹C. The distribution and kinetics of [¹¹C]trimebutine in health rats and rats with an orthotopic C6 glioma were evaluated by ex-vivo gamma counting and positron emission tomography, respectively. Blocking experiments with an excess of unlabeled trimebutine or the μ-opioid receptor ligand cyprodime were employed to determine if trimebutine exhibits saturable binding in the brain. In addition, plasma stability of the tracer was assessed.</p><p><strong>Results: </strong>The proliferation assay and cell scratch healing assay confirmed that trimebutine has anti-tumor effects in-vitro. [¹¹C]Trimebutine with a radiochemical purity >98 % was synthesized in 15 ± 5 % radiochemical yield. In peripheral organs, the highest accumulation of the tracer was detected in excretion organs. In the brain, the highest tracer uptake was observed in the brainstem and the lowest in the hypothalamus, although differences between regions were small. PET imaging showed rapid brain uptake of [¹¹C]trimebutine, followed by a gradual washout. Administration of an intravenous dose of trimebutine (10 mg/kg) significantly decreased the uptake in all brain regions (p < 0.05), except midbrain. Likewise, administration of cyprodime (2 mg/kg) significantly reduced [¹¹C]trimebutine uptake in the brain (p < 0.01). However, uptake of [¹¹C]trimebutine in the tumor was not significantly different from its brain uptake in rats bearing an orthotopic C6 glioma. The percentage of intact [¹¹C]trimebutine at 60 min post injection was only 1.7 ± 0.6 %.</p><p><strong>Conclusion: </strong>Trimebutine exhibits inhibitory effects on the growth and migration of glioma cells in a dose- and time-dependent manner. [¹¹C]Trimebutine was able to penetrate the blood-brain barrier in rats and tracer uptake could be significantly reduced by administration of a μ-opioid receptor antagonist. However, [¹¹C]trimebutine failed to selectively accumulate in orthotopic C6 glioma, which could be caused by low expression levels of the drug target in these tumors, or by fast metabolism of the tracer.</p>","PeriodicalId":19363,"journal":{"name":"Nuclear medicine and biology","volume":"142-143 ","pages":"108985"},"PeriodicalIF":3.6,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142813842","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transmembrane protein 106B amyloid is a potential off-target molecule of tau PET tracers in the choroid plexus.","authors":"Yuka Yokoyama, Ryuichi Harada, Kaede Kudo, Ren Iwata, Yukitsuka Kudo, Nobuyuki Okamura, Shozo Furumoto","doi":"10.1016/j.nucmedbio.2024.108986","DOIUrl":"https://doi.org/10.1016/j.nucmedbio.2024.108986","url":null,"abstract":"<p><strong>Purpose: </strong>Tau positron emission tomography (PET) has become an essential tool for the clinical diagnosis of neurodegenerative diseases and the study of tau pathology in the brain. However, some tau tracers exhibit off-target binding in the basal ganglia, choroid plexus, and meninges. Recently, transmembrane protein 106B (TMEM106B) was identified to form novel amyloid filaments in the brain during aging. In this study, we explored the possibility that TMEM106B aggregates might be responsible for off-target binding of tau PET tracers in the choroid plexus.</p><p><strong>Methods: </strong>The binding properties of ¹⁸F-labeled tau and amyloid tracers against choroid plexus tissues from postmortem human brains were evaluated through in vitro autoradiography and in vitro binding assays and compared with histochemical staining.</p><p><strong>Results: </strong>Autoradiography showed strong binding of [¹⁸F]PM-PBB3 followed by [¹⁸F]flortaucipir in the choroid plexus. Immunostaining of the same sections revealed a high level of transmembrane protein 106B aggregates, which are thioflavin-S-labeled Biondi ring structures, in the choroid plexus epithelium and co-localization with PM-PBB3-stained structures. In contrast, co-localization of flortaucipir with TMEM106B immunoreactivity was not confirmed because flortaucipir had a low fluorescence intensity. In vitro binding assays for [¹⁸F]PM-PBB3 and [¹⁸F]flortaucipir demonstrated high affinities for collagenase A-treated choroid plexus homogenate containing transmembrane protein 106B aggregates.</p><p><strong>Conclusion: </strong>This study demonstrated high affinity of [¹⁸F]PM-PBB3 for TMEM106B aggregates in the choroid plexus. In vivo off-target binding of [¹⁸F]PM-PBB3 to the choroid plexus might result from binding to TMEM106B aggregates.</p>","PeriodicalId":19363,"journal":{"name":"Nuclear medicine and biology","volume":"142-143 ","pages":"108986"},"PeriodicalIF":3.6,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142795073","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"225Aс/213Bi generator for direct synthesis of 213Bi-labeled bioconjugates","authors":"Stanislav V. Ermolaev ,&nbsp;Aleksandr N. Vasiliev ,&nbsp;Aino K. Skasyrskaya ,&nbsp;Elena V. Lapshina ,&nbsp;Daria R. Khaliullina ,&nbsp;Olga N. Libanova","doi":"10.1016/j.nucmedbio.2024.108975","DOIUrl":"10.1016/j.nucmedbio.2024.108975","url":null,"abstract":"<div><h3>Background</h3><div>²¹³Bi is a short-lived radionuclide currently trialed for alpha therapy of various oncological diseases. A serious obstacle to the wide medical use is decay losses of ²¹³Bi during a conventional synthesis of radiopharmaceuticals. In this work, we aimed to develop a two-column ²²⁵Aс/²¹³Bi generator providing the accumulation of ²¹³Bi separately from the parent ²²⁵Ac <em>via</em> continuous circular separation and decay of intermediate ²²¹Fr. When attaining the transient equilibrium, ²¹³Bi could be promptly extracted from the generator with an appropriate complexing agent, including chelator-protein bioconjugates.</div></div><div><h3>Methods</h3><div>Sorption behavior of Bi(III) ions onto the cross-linked dextran gel Sephadex G-25 was studied from solutions of hydrochloric and nitric acid, and from sodium chloride, sodium acetate and DTPA solutions. A bifunctional chelating agent p-SCN-Bn-DTPA was conjugated to an antibody Nimotuzumab specific to the epidermal growth factor receptor, and the procedure of ^207,213Bi-DTPA-Nimotuzumab synthesis in the dextran gel medium was developed. The parameters of ²²⁵Aс/²¹³Bi generator system were evaluated.</div></div><div><h3>Results</h3><div>The weight distribution ratios of Bi(III) adsorbed onto the Sephadex G-25 gel were obtained. Up to 85 % of ²¹³Bi was accumulated in the second Sephadex-filled column of ²²⁵Aс/²¹³Bi generator after four-hour circulation of 0.15 M NaCl (pH 5.5) solution. Having passed the solution of DTPA-Nimotuzumab bioconjugate through the second column, a fraction of ²¹³Bi-DTPA-Nimotuzumab radioimmunoconjugate was produced with the radiochemical yield of 64 % ± 3 % (<em>n</em> = 6). High radionuclidic and radiochemical purity of product was achieved.</div></div><div><h3>Conclusions</h3><div>The circulating ²²⁵Aс/²¹³Bi generator provides a ²¹³Bi-labeled bioconjugate as a final product. While a conventional synthesis route including generator milking, bioconjugate labeling and size-exclusion purification takes &gt;20 min, the duration of ²¹³Bi-DTPA-Nimotuzumab production by the method proposed in this work is reduced to 6–8 min.</div></div>","PeriodicalId":19363,"journal":{"name":"Nuclear medicine and biology","volume":"140 ","pages":"Article 108975"},"PeriodicalIF":3.6,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142697880","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pretargeted alpha therapy in MUC16-positive high-grade serous ovarian cancer","authors":"Kyeara N. Mack ,&nbsp;David Bauer ,&nbsp;Lukas M. Carter ,&nbsp;Sebastian E. Carrasco ,&nbsp;Mohamed I. Atmane ,&nbsp;Tara D. Viray ,&nbsp;Cory L. Brooks ,&nbsp;Michael A. Hollingsworth ,&nbsp;Prakash Radhakrishnan ,&nbsp;Jason S. Lewis","doi":"10.1016/j.nucmedbio.2024.108976","DOIUrl":"10.1016/j.nucmedbio.2024.108976","url":null,"abstract":"<div><h3>Background</h3><div>Peritoneal metastasis with micrometastatic cell clusters is a common feature of advanced ovarian cancer. Targeted alpha therapy (TAT) is an attractive approach for treating micrometastatic diseases as alpha particles release enormous amounts of energy within a short distance. A pretargeting approach — leveraging the inverse-electron-demand Diels-Alder reaction between tetrazines (Tz) and trans-cyclooctene (TCO) — can minimize off-target toxicity related to TAT, often associated with full-length antibodies. We hypothesized that a pretargeting strategy could effectively treat high-grade serous (HGS) ovarian tumors while minimizing toxicity.</div></div><div><h3>Methods</h3><div>We utilized the humanized antibody, AR9.6, labeled with actinium-225 (²²⁵Ac). AR9.6 targets fully glycosylated and hypoglycosylated isoforms of MUC16. For biodistribution and radioimmunotherapy studies, AR9.6-TCO was injected into OVCAR3-bearing mice 72 h before administering [²²⁵Ac]Ac-mcp-PEG₈-Tz, e.g. using a 1,2,4,5-tetrazine conjugated to the macropa chelator via a polyethylene glycol (PEG) linker.</div></div><div><h3>Results</h3><div>Biodistribution data revealed that the pretargeting approach achieved substantial tumor uptake. Cerenkov luminescence imaging confirmed successful in vivo pretargeting during TAT studies. Compared to the control groups, TAT with AR9.6-TCO and [²²⁵Ac]Ac-mcp-PEG₈-Tz significantly suppressed tumor growth and improved overall survival in OVCAR3 tumor-bearing mice. Renal and ovarian pathology compatible with toxicity was observed in mice in addition to transient hematologic toxicity.</div></div><div><h3>Conclusion</h3><div>We confirmed that pretargeting with AR9.6-TCO and [²²⁵Ac]Ac-mcp-PEG₈-Tz has durable antitumor effects in high MUC16-expressing tumors. These findings demonstrate great potential for using pretargeting in combination with TAT for the treatment of ovarian cancer.</div></div><div><h3>Classification</h3><div>Biological Sciences; Applied Biological Sciences.</div></div>","PeriodicalId":19363,"journal":{"name":"Nuclear medicine and biology","volume":"140 ","pages":"Article 108976"},"PeriodicalIF":3.6,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142748091","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}