Nuclear medicine and biology最新文献

{"title":"Alpha Atlas: Mapping global production of α-emitting radionuclides for targeted alpha therapy","authors":"Marianna Tosato ,&nbsp;Chiara Favaretto ,&nbsp;Janke Kleynhans ,&nbsp;Andrew R. Burgoyne ,&nbsp;Jean-François Gestin ,&nbsp;Nicholas P. van der Meulen ,&nbsp;Amirreza Jalilian ,&nbsp;Ulli Köster ,&nbsp;Mattia Asti ,&nbsp;Valery Radchenko","doi":"10.1016/j.nucmedbio.2024.108990","DOIUrl":"10.1016/j.nucmedbio.2024.108990","url":null,"abstract":"<div><div>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.</div><div>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.</div></div>","PeriodicalId":19363,"journal":{"name":"Nuclear medicine and biology","volume":"142 ","pages":"Article 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":"OA","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 ,&nbsp;Jason C. Mixdorf ,&nbsp;Johan Svedjehed ,&nbsp;Jeanine Batterton ,&nbsp;Jennifer Eagleburger ,&nbsp;Yongjun Yan ,&nbsp;Katherine Gagnon ,&nbsp;Eduardo Aluicio-Sarduy ,&nbsp;Todd E. Barnhart ,&nbsp;Jonathan W. Engle","doi":"10.1016/j.nucmedbio.2024.108989","DOIUrl":"10.1016/j.nucmedbio.2024.108989","url":null,"abstract":"<div><div>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 % (<em>n</em> = 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 % (<em>n</em> = 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.</div></div>","PeriodicalId":19363,"journal":{"name":"Nuclear medicine and biology","volume":"142 ","pages":"Article 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 ,&nbsp;Maria Kominia ,&nbsp;Janine Doorduin ,&nbsp;Erik F.J. de Vries","doi":"10.1016/j.nucmedbio.2024.108985","DOIUrl":"10.1016/j.nucmedbio.2024.108985","url":null,"abstract":"<div><h3>Purpose</h3><div>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.</div></div><div><h3>Method</h3><div>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.</div></div><div><h3>Results</h3><div>The proliferation assay and cell scratch healing assay confirmed that trimebutine has anti-tumor effects in-vitro. [¹¹C]Trimebutine with a radiochemical purity &gt;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 (<em>p</em> &lt; 0.05), except midbrain. Likewise, administration of cyprodime (2 mg/kg) significantly reduced [¹¹C]trimebutine uptake in the brain (<em>p</em> &lt; 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 %.</div></div><div><h3>Conclusion</h3><div>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.</div></div>","PeriodicalId":19363,"journal":{"name":"Nuclear medicine and biology","volume":"142 ","pages":"Article 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":"OA","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 ,&nbsp;Ryuichi Harada ,&nbsp;Kaede Kudo ,&nbsp;Ren Iwata ,&nbsp;Yukitsuka Kudo ,&nbsp;Nobuyuki Okamura ,&nbsp;Shozo Furumoto","doi":"10.1016/j.nucmedbio.2024.108986","DOIUrl":"10.1016/j.nucmedbio.2024.108986","url":null,"abstract":"<div><h3>Purpose</h3><div>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.</div></div><div><h3>Methods</h3><div>The binding properties of ¹⁸F-labeled tau and amyloid tracers against choroid plexus tissues from postmortem human brains were evaluated through <em>in vitro</em> autoradiography and <em>in vitro</em> binding assays and compared with histochemical staining.</div></div><div><h3>Results</h3><div>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. <em>In vitro</em> binding assays for [¹⁸F]PM-PBB3 and [¹⁸F]flortaucipir demonstrated high affinities for collagenase A-treated choroid plexus homogenate containing transmembrane protein 106B aggregates.</div></div><div><h3>Conclusion</h3><div>This study demonstrated high affinity of [¹⁸F]PM-PBB3 for TMEM106B aggregates in the choroid plexus. <em>In vivo</em> off-target binding of [¹⁸F]PM-PBB3 to the choroid plexus might result from binding to TMEM106B aggregates.</div></div>","PeriodicalId":19363,"journal":{"name":"Nuclear medicine and biology","volume":"142 ","pages":"Article 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":"OA","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}

{"title":"In vitro and in vivo study of 221Fr and 213Bi progeny release from the 225Ac-labelled TiO2 nanoparticles","authors":"Michal Sakmár ,&nbsp;Ján Kozempel ,&nbsp;Jan Kučka ,&nbsp;Tereza Janská ,&nbsp;Matěj Štíbr ,&nbsp;Lukáš Ondrák ,&nbsp;Kateřina Ondrák Fialová ,&nbsp;Martin Vlk ,&nbsp;Luděk Šefc ,&nbsp;Frank Bruchertseifer ,&nbsp;Alfred Morgenstern","doi":"10.1016/j.nucmedbio.2024.108973","DOIUrl":"10.1016/j.nucmedbio.2024.108973","url":null,"abstract":"<div><h3>Background</h3><div>Targeted alpha therapy (TAT) is an effective option for cancer treatment. To maximize its efficacy and minimize side effects, carriers must deliver radionuclides to target tissues. Most of the nuclides used in TAT decay <em>via</em> the alpha cascade, producing several radioactive daughter nuclei with sufficient energy to escape from the original carrier. Therefore, studying these daughter atoms is crucial in the search for new carriers. Nanoparticles have potential as carriers due to their structure, which can prevent the escape of daughter atoms and reduce radiation exposure to non-target tissues. This work focuses on determining the released activity of ²²¹Fr and ²¹³Bi resulting from the decay of ²²⁵Ac labelled TiO₂ nanoparticles.</div></div><div><h3>Results</h3><div>Labelling of TiO₂ nanoparticles has shown high sorption rates of ²²⁵Ac and its progeny, ²²¹Fr and ²¹³Bi, with over 92 % of activities sorbed on the nanoparticle surface for all measured radionuclides. However, in the quasi-dynamic <em>in vitro</em> system, the released activity of ²²¹Fr and ²¹³Bi is strongly dependent on the nanoparticles concentration, ranging from 15 % for a concentration of 1 mg/mL to approximately 50 % for a nanoparticle concentration of 10 μg/mL in saline solution. The released activities of ²¹³Bi were lower, with a maximum value of around 20 % for concentrations of 0.05, 0.025, and 0.01 mg/mL. The leakage of ²²⁵Ac and its progeny was tested in various biological matrices. Minimal released activity was measured in saline at around 10 % after 48 h, while the maximum activity was measured in blood serum and plasma at 20 %. The amount of ²²⁵Ac released into the media was minimal (&lt;3 %). The <em>in vitro</em> results were confirmed in a healthy mouse model. The difference in %ID/g was clearly visible immediately after dissection and again after 6 h when ²¹³Bi reached equilibrium with ²²⁵Ac.</div></div><div><h3>Conclusion</h3><div>The study verified the potential release of ²²⁵Ac progeny from the labelled TiO₂ nanoparticles. Experiments were performed to determine the dependence of released activity on nanoparticle concentration and the biological environment. The results demonstrated the high stability of the prepared ²²⁵Ac@TiO₂ NPs and the potential release of progeny over time. <em>In vivo</em> studies confirmed our hypothesis. The data obtained suggest that the daughter atoms can escape from the original carrier and follow their own biological pathways in the organism.</div></div>","PeriodicalId":19363,"journal":{"name":"Nuclear medicine and biology","volume":"140 ","pages":"Article 108973"},"PeriodicalIF":3.6,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142695742","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":"The potential of targeted radionuclide therapy to treat hypoxic tumor cells","authors":"S.T.M. Wenker ,&nbsp;S.A.M. van Lith ,&nbsp;G. Tamborino ,&nbsp;M.W. Konijnenberg ,&nbsp;J. Bussink ,&nbsp;S. Heskamp","doi":"10.1016/j.nucmedbio.2024.108971","DOIUrl":"10.1016/j.nucmedbio.2024.108971","url":null,"abstract":"<div><div>Tumor hypoxia contributes to cancer progression and therapy resistance. Several strategies have been investigated to relieve tumor hypoxia, of which some were successful. However, their clinical application remains challenging and therefore they are not used in daily clinical practice. Here, we review the potential of targeted radionuclide therapy (TRT) to eradicate hypoxic cancer cells. We present an overview of the published TRT strategies using β^‐-particles, α-particles, and Auger electrons. Altogether, we conclude that α-particle emitting radionuclides are most promising since they can cause DNA double strand breaks independent of oxygen levels. Future directions for research are addressed, including more adequate <em>in vitro</em> and <em>in vivo</em> models to proof the potential of TRT to eliminate hypoxic cancer cells. Furthermore, dosimetry and radiobiology are identified as key to better understand the mechanism of action and dose-response relationships in hypoxic tumor areas. Finally, we can conclude that in order to achieve long-term anti-tumor efficacy, TRT combination treatment strategies may be necessary.</div></div>","PeriodicalId":19363,"journal":{"name":"Nuclear medicine and biology","volume":"140 ","pages":"Article 108971"},"PeriodicalIF":3.6,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142695745","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluation of chelating agents based on pyridine-azacrown compounds H4PATA, PATAM, and H4PATPA for 68Ga and 177Lu","authors":"Anna A. Shchukina ,&nbsp;Anastasia D. Zubenko ,&nbsp;Oksana V. Tarasenko ,&nbsp;Anton A. Larenkov ,&nbsp;Viktor B. Bubenshchikov ,&nbsp;Ekaterina Y. Chernikova ,&nbsp;Yury V. Fedorov ,&nbsp;Olga A. Fedorova","doi":"10.1016/j.nucmedbio.2024.108972","DOIUrl":"10.1016/j.nucmedbio.2024.108972","url":null,"abstract":"<div><div>In this article, we present the synthesis and characterization of three macrocyclic chelators, <strong>H</strong>_{<strong>4</strong>}<strong>PATA</strong>, <strong>PATAM</strong>, and <strong>H</strong>_{<strong>4</strong>}<strong>PATPA</strong>, based on a pyridine-azacrown compound. Their complexation with ⁶⁸Ga and ¹⁷⁷Lu has been thoroughly investigated using MALDI TOF MS, ¹H NMR spectroscopy, radiolabeling studies, and experiments <em>in vitro</em> with fetal bovine serum and a 1000-fold molar excess of <strong>H</strong>_{<strong>4</strong>}<strong>EDTA</strong>. Our studies have shown that the chelators <strong>H</strong>_{<strong>4</strong>}<strong>PATA</strong> and <strong>H</strong>_{<strong>4</strong>}<strong>PATPA</strong> form complexes at room temperature with both radionuclides (RCY &gt; 80 % and &gt; 90 % for complexes with <strong>H</strong>_{<strong>4</strong>}<strong>PATA</strong> and <strong>H</strong>_{<strong>4</strong>}<strong>PATPA</strong> after 30 min, respectively). The chelator <strong>PATAM</strong> requires high temperature (95 °C) for complexation. <em>In vitro</em> stability assays in fetal bovine serum as well as <strong>H</strong>_{<strong>4</strong>}<strong>EDTA</strong>-challenge revealed that transchelation occurs for all complexes with ⁶⁸Ga. However, complexes of the ligands <strong>H</strong>_{<strong>4</strong>}<strong>PATA</strong> and <strong>PATAM</strong> with ¹⁷⁷Lu were found stable. Thus, taking into account the radiolabeling at room temperature and <em>in vitro</em> stability of the complex [¹⁷⁷Lu]Lu·<strong>PATA</strong>, our investigations revealed the chelator <strong>H</strong>_{<strong>4</strong>}<strong>PATA</strong> is a candidate for radiopharmaceutical use with ¹⁷⁷Lu.</div></div>","PeriodicalId":19363,"journal":{"name":"Nuclear medicine and biology","volume":"140 ","pages":"Article 108972"},"PeriodicalIF":3.6,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142648134","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":"New prospects for 89Zr-immuno-PET in brain applications – Alpha-synucleinopathies","authors":"Thomas E. Wuensche ,&nbsp;Pedro M. Pereira ,&nbsp;Albert D. Windhorst ,&nbsp;Kaare Bjerregaard-Andersen ,&nbsp;Florence Sotty ,&nbsp;Pekka Kallunki ,&nbsp;Allan Jensen ,&nbsp;Benny Bang-Andersen ,&nbsp;Guus A.M.S. van Dongen ,&nbsp;Wissam Beaino ,&nbsp;Danielle J. Vugts","doi":"10.1016/j.nucmedbio.2024.108969","DOIUrl":"10.1016/j.nucmedbio.2024.108969","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;div&gt;Recently, &lt;sup&gt;89&lt;/sup&gt;Zr-immuno-PET imaging of therapeutic antibodies, actively transported over the blood-brain-barrier &lt;em&gt;via&lt;/em&gt; transferrin-mediated transcytosis, was demonstrated using the chelator DFO*. In these studies, aducanumab targeting amyloid-beta was fused with a transferrin binding unit: a single-chain Fab fragment derived from 8D3 (scFab8D3). Alpha-synuclein is a hallmark protein of several neurodegenerative diseases such as Parkinson's Disease, Lewy-Body-Dementia, and Multiple System Atrophy. &lt;sup&gt;89&lt;/sup&gt;Zr-immuno-PET imaging of alpha-synuclein can be a valuable tool for image-guided drug development and assessment of target engagement. The goal of this study was to compare two currently used constructs of 8D3 for targeting potential, namely a single moiety of scFab8D3 fused to the alpha-synuclein antibody HLu-3 (HLu-3-scFab8D3) &lt;em&gt;versus&lt;/em&gt; HLu-3 fused with two 8D3 single-chain variable fragments (HLu-3-(scFv8D3)&lt;sub&gt;2&lt;/sub&gt;), by &lt;sup&gt;89&lt;/sup&gt;Zr-immuno-PET in an alpha-synuclein pre-formed fibril (PFF) deposition model. HLu-3 and the HIV-targeting B12-scFab8D3 were used as controls. The best-performing compound was further investigated in an animal model with predominantly intraneural target aggregation.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;Antibodies were conjugated with DFO* using DFO*-NCS and subsequently radiolabeled with &lt;sup&gt;89&lt;/sup&gt;Zr. Assessment of binding affinity was done by alpha-synuclein ELISA and with FACS analysis using mTfR1 expressing CHO-S cells. Radioimmunoconjugates were first evaluated in an extracellular alpha-synuclein deposition model established by intracranial injection of non-sonicated PFFs into the left striatum of C57Bl/6 WT mice, whereas saline was injected into the contralateral site as control. PET imaging was performed 1, 3, and 7 days post-injection, followed by &lt;em&gt;ex vivo&lt;/em&gt; biodistribution, autoradiography and immunofluorescence analysis. Based on the results from these studies, the better-performing antibody candidate was tested similarly in an alpha-synuclein seeding model. The seeding model has intraneural alpha-synuclein aggregation and was established by intracranial injection of sonicated PFFs into both striata of F28tg mice, which overexpress human wild-type alpha-synuclein. Untreated F28tg and C57Bl/6 WT mice served as controls.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;The radioimmunoconjugate was produced in sufficient radiochemical yields and purity. There was no impairment of binding affinity towards alpha-synuclein, and acceptable binding with negligible losses to mTfR1. PET imaging with [&lt;sup&gt;89&lt;/sup&gt;Zr]Zr-HLu-3-scFab8D3 and [&lt;sup&gt;89&lt;/sup&gt;Zr]Zr-HLu-3-(scFv8D3)&lt;sub&gt;2&lt;/sub&gt; in the deposition model showed uptake at the site of alpha-synuclein deposits. However, uptake was variable between mice. Reliable PET quantification was hampered due to the small deposition volume (~2 μL). Immunofluorescence revealed specific alpha-synuclein target engagement of","PeriodicalId":19363,"journal":{"name":"Nuclear medicine and biology","volume":"140 ","pages":"Article 108969"},"PeriodicalIF":3.6,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142697881","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}