Nuclear medicine and biology最新文献

{"title":"Radiobiological effect of alpha particles. The scientific basis of targeted alpha-particle therapy","authors":"Pedro Cruz-Nova ,&nbsp;Maydelid Trujillo-Nolasco ,&nbsp;Liliana Aranda-Lara ,&nbsp;Guillermina Ferro-Flores ,&nbsp;Blanca Ocampo-García","doi":"10.1016/j.nucmedbio.2025.109044","DOIUrl":"10.1016/j.nucmedbio.2025.109044","url":null,"abstract":"<div><div>Targeted alpha therapy (TAT) uses alpha-emitting radionuclides to deliver high-energy radiation directly to a specific biological target. TAT has shown promising results in the treatment of advanced metastatic disease and has demonstrated greater efficacy than beta radiation in inducing apoptosis, mutations, carcinogenesis, chromosomal aberrations, and chromosomal instability. The biological effects of alpha particle radiation are associated with the high energy delivered over short distances, producing high levels of reactive oxygen and nitrogen species. Likewise, alpha particle radiation induces more mutations per median lethal dose compared to beta particles and promotes the accumulation of substitutions and indels. Identification of novel early response genes to alpha particles is critical for understanding the molecular mechanisms underlying genomic damage, cell death, and potentially latent malignant transformation.</div><div>This review provides an overview of the biological effects of alpha particle exposure, with the aim of enhancing the understanding, research, and development of alpha-emitter-based radiopharmaceuticals. It also discusses anti-tumor immune responses, the induction of inflammatory cell death, alpha particle-cell membrane interactions, and the bystander effect. Dosimetry aspects were not covered in this review.</div></div>","PeriodicalId":19363,"journal":{"name":"Nuclear medicine and biology","volume":"146 ","pages":"Article 109044"},"PeriodicalIF":3.6,"publicationDate":"2025-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144331205","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":"Trithiol ligand provides tumor-targeting 191Pt-complexes with high molar activity and promising in vivo properties","authors":"Honoka Obata ,&nbsp;Atsushi B. Tsuji ,&nbsp;Yutian Feng ,&nbsp;Yongxiang Zheng ,&nbsp;Hitomi Sudo ,&nbsp;Aya Sugyo ,&nbsp;Werner Tornow ,&nbsp;Sean W. Finch ,&nbsp;Katsuyuki Minegishi ,&nbsp;Hisashi Suzuki ,&nbsp;Jun Ichinose ,&nbsp;Mikako Ogawa ,&nbsp;Ming-Rong Zhang ,&nbsp;Michael R. Zalutsky","doi":"10.1016/j.nucmedbio.2025.109043","DOIUrl":"10.1016/j.nucmedbio.2025.109043","url":null,"abstract":"<div><h3>Purpose</h3><div>The Auger electron-emitting radionuclide ¹⁹¹Pt is a promising candidate for radiopharmaceutical therapy. Herein, we explored novel labeling methods for ¹⁹¹Pt using thiol-containing ligands to improve the in vivo stability and targeting ability of ¹⁹¹Pt-labeled complexes.</div></div><div><h3>Methods</h3><div>We synthesized dithiol-containing N₂S₂ and NS₂ ligands, and a trithiol ligand, and then compared their radiochemical reactivity with ¹⁹¹Pt. [¹⁹¹Pt]Pt-trithiol was synthesized and its biodistribution was evaluated in mice and compared with free ¹⁹¹Pt. Finally, a ¹⁹¹Pt-trithiol complex targeting prostate-specific membrane antigen (PSMA): [¹⁹¹Pt]Pt-trithiol-PSMA was developed and evaluated in mice bearing tumor xenografts and compared with a ¹⁹¹Pt-complex labeled via monothiol-containing Cys ([¹⁹¹Pt]Pt-Cys-PSMA).</div></div><div><h3>Results</h3><div>A comparison of N₂S₂, NS₂, and trithiol showed that the trithiol ligand is the best for producing ¹⁹¹Pt-labeled compounds in high yield and as a single peak in preparative HPLC. Notably, the trithiol ligand made ¹⁹¹Pt-labeled compounds and precursors separatable, achieving ¹⁹¹Pt-labeled products with a high molar activity: 200–400 mCi/μmol (7.4–14.8 GBq/μmol) at EOS. Additionally, [¹⁹¹Pt]Pt-trithiol and [¹⁹¹Pt]Pt-trithiol-PSMA were stable in vivo with rapid clearance compared with free ¹⁹¹Pt and [¹⁹¹Pt]Pt-Cys-PSMA. [¹⁹¹Pt]Pt-trithiol-PSMA resulted in a low uptake in most normal organs and a high uptake in the kidneys and prostate cancer with PSMA expression.</div></div><div><h3>Conclusions</h3><div>This study demonstrated that a labeling method with trithiol for Pt radionuclides achieves ¹⁹¹Pt-labeled products with high molar activity. ¹⁹¹Pt-trithiol-PSMA showed promising in vivo stability and tumor-targeting specificity, which should facilitate the pharmaceutical development of Pt radionuclides for radiopharmaceutical therapy, especially Auger electron cancer therapy.</div></div>","PeriodicalId":19363,"journal":{"name":"Nuclear medicine and biology","volume":"146 ","pages":"Article 109043"},"PeriodicalIF":3.6,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144306561","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":"A novel synergistic drug combination of a mitogen-activated extracellular signal-regulated kinase inhibitor with [177Lu]Lu-rhPSMA-10.1 for prostate cancer treatment: Results of a preclinical evaluation","authors":"Caroline Foxton ,&nbsp;Bart Cornelissen ,&nbsp;Edward O'Neill ,&nbsp;Bradley Waldron ,&nbsp;Freja Pretzmann ,&nbsp;Rikke Veggerby Grønlund ,&nbsp;Mathias Wikke Hallund ,&nbsp;Daniel J. Stevens","doi":"10.1016/j.nucmedbio.2025.109042","DOIUrl":"10.1016/j.nucmedbio.2025.109042","url":null,"abstract":"<div><h3>Purpose</h3><div>The prostate-specific membrane antigen (PSMA)-targeted radiohybrid ligand [¹⁷⁷Lu]Lu-rhPSMA-10.1 is a promising next-generation radiopharmaceutical therapy in prostate cancer. This preclinical evaluation comprised an <em>in vitro</em> screen of potential novel synergistic drug combinations with [¹⁷⁷Lu]Lu-rhPSMA-10.1, and an <em>in vivo</em> efficacy analysis of the lead drug combination in PSMA-expressing prostate cancer xenografts.</div></div><div><h3>Methods</h3><div>In total, 177 anticancer drugs were screened in a clonogenic survival assay of 22Rv1 cells which used 5-fold serial dilutions of the test drug (≤ 20 μM) to determine the half-maximal inhibitory concentration (IC₅₀), compared to incubations of the test drug plus [¹⁷⁷Lu]Lu-rhPSMA-10.1 (15 MBq) after 10 days. A subsequent focused screen assessed the impact of [¹⁷⁷Lu]Lu-rhPSMA-10.1 (0–25 MBq/mL) on drug IC₅₀. Synergy scores were determined using the zero interaction potency (ZIP) reference model (ZIP scores &gt;5 % indicate high synergistic potency) and the multidimensional synergy of combinations (MuSyC) platform (log α &gt;0 indicates synergistic potency). Therapeutic efficacy of the lead drug combination was evaluated <em>in vivo</em>: intravenous [¹⁷⁷Lu]Lu-rhPSMA-10.1 (30 MBq, single dose) and oral cobimetinib (0.25 mg/day for 21 days) (alone/in combination) were administered to 22Rv1 tumor-bearing NMRI nude mice (eight mice/group plus untreated controls). Tumor volume was measured twice weekly for 69 days (two-way ANOVA and Tukey's multiple comparisons test: data analyzed until three mice/group remained). KaplanMeier Log-rank survival analyses were performed.</div></div><div><h3>Results</h3><div><em>In vitro</em> screening identified cobimetinib (a mitogen-activated extracellular signal-regulated kinase inhibitor) as a lead candidate for synergistic combination with [¹⁷⁷Lu]Lu-rhPSMA-10.1 across a wide concentration range (ZIP score=13 %). MuSyC analysis suggested synergistic efficacy from enhanced potency of both drugs in the combination (both log α&gt;3). Combination treatment significantly suppressed tumor growth <em>in vivo versus</em> untreated controls (from Day 13–30; <em>p</em>&lt;0.01) and [¹⁷⁷Lu]Lu-rhPSMA-10.1 (from Day 17–30; <em>p</em>&lt;0.001). Median survival was significantly longer with combination treatment (49 days) <em>versus</em> untreated controls (23 days; <em>p</em>=0.001) and [¹⁷⁷Lu]Lu-rhPSMA-10.1 monotherapy (36 days; <em>p</em>=0.002). No major compound-related toxicity for cobimetinib ± [¹⁷⁷Lu]Lu-rhPSMA-10.1 was observed.</div></div><div><h3>Conclusions</h3><div>The combination of cobimetinib and [¹⁷⁷Lu]Lu-rhPSMA-10.1 demonstrated enhanced preclinical therapeutic efficacy <em>versus</em> single agents, supporting clinical investigation of this novel drug combination in prostate cancer.</div></div>","PeriodicalId":19363,"journal":{"name":"Nuclear medicine and biology","volume":"146 ","pages":"Article 109042"},"PeriodicalIF":3.6,"publicationDate":"2025-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144280366","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":"Comparative evaluation of radiolabeled bombesin analogs [177Lu]Lu-AMBA and [177Lu]Lu-RM2 for targeting GRPR in glioblastoma model","authors":"Michal Grzmil ,&nbsp;Muriel Aline Spahn ,&nbsp;Philipp Berger ,&nbsp;Roger Schibli ,&nbsp;Martin Béhé","doi":"10.1016/j.nucmedbio.2025.109041","DOIUrl":"10.1016/j.nucmedbio.2025.109041","url":null,"abstract":"<div><h3>Introduction</h3><div>Radiolabeled agonist ligands bind to and activate target receptors, inducing internalization and delivering radionuclides into the inner cancer cells. In contrast, receptor-bound antagonizing radiopeptides inhibit receptor signaling and remain outside of the cells, but often show more favorable pharmacokinetics. Our head-to-head preclinical comparison of the gastrin-releasing peptide receptor (GRPR) antagonist and the agonist radioligands was conducted in a human glioblastoma (GBM) model.</div></div><div><h3>Methods</h3><div>The cellular uptake of lutetium-177 labeled agonist [¹⁷⁷Lu]Lu-AMBA and antagonist [¹⁷⁷Lu]Lu-RM2 was evaluated through internalization assays in human GBM U-251 and breast cancer T47-D cells. Immunohistochemistry for γH2AX and the 2′,7′-dichlorofluorescein-diacetate (DCFH-DA) probe were used to assess the induction of DNA double strand breaks (DSB) and generation of reactive oxygen species (ROS), respectively. An <em>in vivo</em> biodistribution study of the radiopeptides was conducted using U-251 xenografted nude mice. <em>Results</em>: Both [¹⁷⁷Lu]Lu-AMBA and [¹⁷⁷Lu]Lu-RM2 showed GRPR-specific uptake, whereby [¹⁷⁷Lu]Lu-AMBA was internalized in contrast to [¹⁷⁷Lu]Lu-RM2, which remained bound to the cell membrane. <em>In vitro</em> studies showed no significant difference in the total cellular uptake of radiopeptides. [¹⁷⁷Lu]Lu-RM2 binding to the receptor was blocked by the unlabeled AMBA ligand. Quantification of [¹⁷⁷Lu]Lu-AMBA and [¹⁷⁷Lu]Lu-RM2-induced DSB and ROS levels revealed no significant difference in treated cells. <em>In vivo</em>, biodistribution showed increased tumor uptake of [¹⁷⁷Lu]Lu-RM2 compared to [¹⁷⁷Lu]Lu-AMBA, whereby washout from receptor positive organs like pancreas, intestine, stomach, and spleen were significantly faster in [¹⁷⁷Lu]Lu-RM2-treated mice.</div></div><div><h3>Conclusion</h3><div>This study established targeting GRPR with both agonist and antagonist radioligands in glioma U-251 <em>in vitro</em> and <em>in vivo</em> models and recommends further development of antagonizing radiolabeled bombesin analog RM2, which showed <em>in vivo</em> superiority in tumor uptake and tumor-to-normal organ ratios (TNRs) over agonist AMBA radioligand.</div></div>","PeriodicalId":19363,"journal":{"name":"Nuclear medicine and biology","volume":"146 ","pages":"Article 109041"},"PeriodicalIF":3.6,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144280365","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 [225Ac]Ac-PSMA-617 and in vivo effect comparison in combination with [177Lu]Lu-PSMA-617 for prostate cancer","authors":"E. Savio,&nbsp;L. Reyes,&nbsp;J. Giglio,&nbsp;L. Alfaya,&nbsp;G. Falasco,&nbsp;L. Urrutia,&nbsp;M. Bentura,&nbsp;K. Zirbesegger,&nbsp;F. Arredondo,&nbsp;P. Duarte,&nbsp;J.P. Gambini,&nbsp;R. Dapueto","doi":"10.1016/j.nucmedbio.2025.109032","DOIUrl":"10.1016/j.nucmedbio.2025.109032","url":null,"abstract":"<div><h3>Introduction</h3><div>The interest in targeted alpha therapy (TAT) has grown in the recent years as it can provide new treatment options for advanced- and late-stage cancer. In this sense, the use of actinium-225 is rising showing promising results. Even more, combining alpha and beta (lutetium-177) radionuclides might help to minimize actinium adverse effects, while preserving treatment efficacy. Preclinical studies of actinium-225-PSMA-targeting tracers for advanced prostate cancer and the “cocktail” combination with lutetium-177-PSMA needs to be further explored.</div></div><div><h3>Methods</h3><div><em>In vitro</em> properties of [²²⁵Ac]Ac-PSMA-617 using the human prostatic cancer cell lines, LNCaP (PSMA+) and PC3 (PSMA-) were investigated by means of antiproliferative, binding, cytotoxicity and clonogenic studies. <em>In vivo</em> de-escalated treatment protocols of actinium-225/lutetium-177-PSMA-617 “cocktail”-regimens were also assessed in order to improve the tolerability of ²²⁵Ac-PSMA-617 TAT. A four-branch study with ([¹⁷⁷Lu]Lu-PSMA-617 and [²²⁵Ac]Ac-PSMA-617) or its combination was successfully performed in a xenographic nude mice model bearing prostate cancer. Tumour growth was monitored by external caliper measurements and PET-CT imaging with [¹⁸F]F-AlF-PSMA-11 over two months.</div></div><div><h3>Results</h3><div>Specific dose-dependent inhibition proliferation of [²²⁵Ac]Ac-PSMA-617 was observed in LNCaP cells (IC₅₀ = 0.14 KBq/mL) whereas an antiproliferative effect in PC3 cells required an activity concentration two orders of magnitude higher (IC₅₀ = 15.5 KBq/mL). In autoradiography binding studies, [²²⁵Ac]Ac-PSMA-617 had significant higher affinity for LNCaP cells, compared to PC3 cells, which probed to be specific under blocking conditions. Cytotoxicity assay evidenced a 200-fold higher toxicity in LNCaP cells. The percentage of colony survival significantly decreased in LNCaP cells treated with 1 KBq/mL and 10 KBq/mL, as compared to PC3 cells treated with the same activity concentrations. The co-administration of both beta and alpha therapeutical radiopharmaceuticals to xenographic nude mice model bearing prostate cancer showed the best results in terms of survival, growth rates and absence of tumour at the endpoint of the study.</div></div><div><h3>Conclusion</h3><div>This study shows that PSMA radioisotope therapy (RIT) and TAT combined therapy could improve patient management by delaying disease progression.</div></div>","PeriodicalId":19363,"journal":{"name":"Nuclear medicine and biology","volume":"146 ","pages":"Article 109032"},"PeriodicalIF":3.6,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144271351","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":"Exploration of the utilization of irreversible cysteine protease inhibitor in FAP-targeted radiopharmaceuticals design to increase tumor residence time","authors":"Katie Brake ,&nbsp;Audifás-Salvador Matus-Meza ,&nbsp;Purnima Rawat ,&nbsp;Pedram Rikhtechi ,&nbsp;Kiana Sherkat Sadi ,&nbsp;Jered C. Garrison","doi":"10.1016/j.nucmedbio.2025.109031","DOIUrl":"10.1016/j.nucmedbio.2025.109031","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Introduction&lt;/h3&gt;&lt;div&gt;Fibroblast activation protein (FAP) is highly upregulated in the stroma of &gt;90 % of epithelial cancers with restricted expression in normal tissues, making it an attractive drug target. Efforts by numerous laboratories developing FAP-targeted radiopharmaceuticals have been significant and led to the development of promising diagnostic agents (e.g., [&lt;sup&gt;68&lt;/sup&gt;Ga]Ga-FAPI-46). However, the poor tumor residence times of many of these low-molecular-weight agents remain a hurdle to radiotherapeutic clinical translation. Our laboratory has been exploring an endolysosomal trapping approach to increase the tumor residence time of radiopharmaceuticals through irreversible adduct formation using epoxysuccinyl peptide inhibitors. Herein, we explore this approach by incorporating an irreversible inhibitor into a FAP-targeted agent, &lt;strong&gt;[&lt;/strong&gt;&lt;sup&gt;&lt;strong&gt;177&lt;/strong&gt;&lt;/sup&gt;&lt;strong&gt;Lu]Lu-FAPI-ET1&lt;/strong&gt;. Along with controls (&lt;strong&gt;[&lt;/strong&gt;&lt;sup&gt;&lt;strong&gt;177&lt;/strong&gt;&lt;/sup&gt;&lt;strong&gt;Lu]Lu-FAPI-SHAM&lt;/strong&gt; and &lt;strong&gt;[&lt;/strong&gt;&lt;sup&gt;&lt;strong&gt;177&lt;/strong&gt;&lt;/sup&gt;&lt;strong&gt;Lu]Lu-FAPI-46&lt;/strong&gt;), the biological performance of &lt;strong&gt;[&lt;/strong&gt;&lt;sup&gt;&lt;strong&gt;177&lt;/strong&gt;&lt;/sup&gt;&lt;strong&gt;Lu]Lu-FAPI-ET1&lt;/strong&gt; was examined through a battery of in vitro and in vivo studies using the FAP-positive human U-87MG glioblastoma cell line as our model.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;&lt;strong&gt;FAPI-ET1&lt;/strong&gt;, &lt;strong&gt;FAPI-SHAM&lt;/strong&gt; and &lt;strong&gt;FAPI-46&lt;/strong&gt; were obtained by multi-step synthesis and radiolabeled using [&lt;sup&gt;177&lt;/sup&gt;Lu]LuCl&lt;sub&gt;3&lt;/sub&gt;. &lt;strong&gt;[&lt;/strong&gt;&lt;sup&gt;&lt;strong&gt;177&lt;/strong&gt;&lt;/sup&gt;&lt;strong&gt;Lu]Lu-FAPI-ET1&lt;/strong&gt; contains the incorporated epoxysuccinyl peptide inhibitor, while &lt;strong&gt;[&lt;/strong&gt;&lt;sup&gt;&lt;strong&gt;177&lt;/strong&gt;&lt;/sup&gt;&lt;strong&gt;Lu]Lu-FAPI-SHAM&lt;/strong&gt; is a nearly identical physiochemical control incapable of adduct formation, and &lt;strong&gt;[&lt;/strong&gt;&lt;sup&gt;&lt;strong&gt;177&lt;/strong&gt;&lt;/sup&gt;&lt;strong&gt;Lu]Lu-FAPI-46&lt;/strong&gt; was used as a clinical benchmark. Western Blot confirmed the FAP expression of U-87MG cells. Kinetics assays of &lt;strong&gt;FAPI-ET1&lt;/strong&gt; and positive control (E-64) were conducted using human cysteine cathepsin B. In vitro IC&lt;sub&gt;50&lt;/sub&gt;, cellular uptake and adduct formation analysis of the three radioconstructs were performed using U-87MG cells. In vivo biodistribution studies were conducted in U-87MG xenograft mouse models, evaluating the constructs at 3-, 24-, 72- and 168-h post-injection time points.&lt;/div&gt;&lt;div&gt;&lt;strong&gt;FAPI-ET1&lt;/strong&gt; and &lt;strong&gt;FAPI-SHAM&lt;/strong&gt; (1.85 ± 0.04 and 0.8 ± 0.7 nM, respectively) exhibited similar FAP binding affinities compared to &lt;strong&gt;FAPI-46 (&lt;/strong&gt;0.9 ± 0.7 nM). &lt;strong&gt;FAPI-ET1&lt;/strong&gt; demonstrated significantly higher cathepsin B inhibition kinetics (120,000 ± 14,000 M&lt;sup&gt;−1&lt;/sup&gt; s&lt;sup&gt;−1&lt;/sup&gt;) than the E-64 inhibitor (42,000 ± 4000 M&lt;sup&gt;−1&lt;/sup&gt; s&lt;sup&gt;−1&lt;/sup&gt;). The cellular uptake, including surface-bound and internalized fraction, of &lt;st","PeriodicalId":19363,"journal":{"name":"Nuclear medicine and biology","volume":"146 ","pages":"Article 109031"},"PeriodicalIF":3.6,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144253502","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":"Synthesis and evaluation of a 99mTc-labelled deuterated tropane derivative as a SPECT probe for dopamine transporter","authors":"Jing Kang ,&nbsp;Jingwen Li ,&nbsp;Chunyi Liu ,&nbsp;Jingjing Hong ,&nbsp;Jiaojiao Zuo ,&nbsp;Yi Fang ,&nbsp;Zhengping Chen","doi":"10.1016/j.nucmedbio.2025.109033","DOIUrl":"10.1016/j.nucmedbio.2025.109033","url":null,"abstract":"<div><h3>Introduction</h3><div>The dopamine transporter (DAT) is intricately associated with a broad spectrum of neurological disorders including Parkinson's disease and various other neurodegenerative conditions. <em>In vivo</em> imaging DAT with radiolabeled tracers has emerged as a prevalent and highly favored approach. This study aims to develop a novel <em>in vivo</em> stable ^99mTc-labelled probe [^99mTc]Tc-TRODAT-d₄ for single photon emission computed tomography (SPECT) for DAT-related disorders with the reported [^99mTc]Tc-TRODAT-1 as the leading compound.</div></div><div><h3>Methods</h3><div>The deuterated labelling precursor for [^99mTc]Tc-TRODAT-d₄ was synthesized and the ^99mTc-labelled radioligand [^99mTc]Tc-TRODAT-d₄ was successfully obtained with radiochemical yield (RCY) &gt; 90 % and radiochemical purity (RCP) &gt; 90 %. <em>In vivo</em> stability of the deuterated probe was evaluated and compared with the non-deuterated [^99mTc]Tc-TRODAT-1 in rodents with radio-HPLC. The specificity and selectivity of the deuterated probe [^99mTc]Tc-TRODAT-d₄ for DAT were assessed through comparative analyses of <em>in vivo</em> biodistribution, blocking experiments, and autoradiography.</div></div><div><h3>Results</h3><div>Biological distribution results revealed that the target-to-non-target ratio (striatum/cerebellum, ST/CB) for [^99mTc]Tc-TRODAT-d₄ surpassed that of [^99mTc]Tc-TRODAT-1 at 120 min post-injection (3.95 ± 0.39 <em>vs</em> 3.05 ± 0.61, <em>p</em> &lt; 0.05). <em>In vivo</em> metabolism investigations demonstrated that [^99mTc]Tc-TRODAT-d₄ exhibits enhanced <em>in vivo</em> stability in mice compared with [^99mTc]Tc-TRODAT-1. <em>Ex vivo</em> autoradiographic findings indicated that [^99mTc]Tc-TRODAT-d₄ selectively accumulated in the DAT-abundant striatum and its ST/CB ratio was higher than that of [^99mTc]Tc-TRODAT-1 (4.11 ± 0.25 <em>vs</em> 3.27 ± 0.09, <em>p</em> &lt; 0.01).</div></div><div><h3>Conclusions</h3><div>A novel <em>in vivo</em> stable ^99mTc-labelled SPECT probe [^99mTc]Tc-TRODAT-d₄ targeting DAT was synthesized by deuteration on [^99mTc]Tc-TRODAT-1 with an RCP of &gt;90 %. The deuterated tracer [^99mTc]Tc-TRODAT-d₄ showed good DAT affinity and specificity. Furthermore, [^99mTc]Tc-TRODAT-d₄ with improved <em>in vivo</em> stability provides a higher target-to-non-target ratio than [^99mTc]Tc-TRODAT-1, giving access to a highly promising ^99mTc-labelled radioligand for SPECT imaging of DAT in the brain.</div></div>","PeriodicalId":19363,"journal":{"name":"Nuclear medicine and biology","volume":"146 ","pages":"Article 109033"},"PeriodicalIF":3.6,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144168483","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":"Radiochemistry of cyclen-derived chelators comprising five-membered azaheterocyclic arms with 212Pb2+, 213Bi3+, and 225Ac3+","authors":"Ina Hierlmeier ,&nbsp;Parmissa Randhawa ,&nbsp;Brooke L. McNeil ,&nbsp;Elisa Oliveri ,&nbsp;Stephan Maus ,&nbsp;Valery Radchenko ,&nbsp;Florian Rosar ,&nbsp;Samer Ezziddin ,&nbsp;Mark D. Bartholomä","doi":"10.1016/j.nucmedbio.2025.109034","DOIUrl":"10.1016/j.nucmedbio.2025.109034","url":null,"abstract":"<div><div>In this work, we introduce the cyclen-based metal chelator DOTThia comprising four methylthiazole arms for metal complexation. Together with the recently described congener DOTI-Me bearing four methylimidazole arms, the radiochemistry of these two compounds with ²¹²Pb, ²¹³Bi, and ²²⁵Ac was investigated thoroughly. Radiolabeling experiments were performed at various pH values and temperatures to determine the optimal conditions for quantitative radiochemical conversions. Experiments revealed excellent complexation properties of DOTThia for ²¹²Pb at room temperature, comparable to those of the current gold standard for Pb complexation, TCMC, while it was not well suited for ²¹³Bi. Contrarily, DOTI-Me exhibited quantitative radiochemical conversions for ²¹³Bi at pH 5.5 and room temperature, outperforming the metal chelator macropa, but was not able to quantitatively complex ²¹²Pb under any conditions investigated. Of note, both novel chelators were not able to bind ²²⁵Ac. In preliminary experiments, we could also show that a functionalized DOTI-Me derivative is capable of complexing ²¹³Bi selectively from ²²⁵Ac solutions. This feature may allow the preparation of ²¹³Bi-labeled radiotracers directly from ²²⁵Ac solutions without the need for an ²²⁵Ac/²¹³Bi generator. However, more detailed studies are needed to fully explore this potential application. Altogether, our results support the future development of ²¹²Pb-labeled radiopharmaceuticals using bifunctional derivatives of DOTThia as well as of ²¹³Bi-labeled radiotracers based on the DOTI-Me scaffold.</div></div>","PeriodicalId":19363,"journal":{"name":"Nuclear medicine and biology","volume":"146 ","pages":"Article 109034"},"PeriodicalIF":3.6,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144184387","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":"Carbon-11-labelling of the histone deacetylase 6 radioligand EKZ-001","authors":"Tetsuro Tago ,&nbsp;Jun Toyohara","doi":"10.1016/j.nucmedbio.2025.109030","DOIUrl":"10.1016/j.nucmedbio.2025.109030","url":null,"abstract":"<div><h3>Purpose</h3><div>Histone deacetylase 6 (HDAC6) is involved in microtubule stabilisation and protein degradation, and is attracting attention as a therapeutic target molecule for neurodegenerative diseases. [¹⁸F]EKZ-001 is a positron emission tomography (PET) radioligand that can visualise HDAC6 in the brain and allows exploration of the relationship between diseases and HDAC6 expression levels and distribution. The present study reports the radiosynthesis of a carbon-11-labelled version of EKZ-001 that is chemically identical to [¹⁸F]EKZ-001. This radiosynthesis adopted a conventional ¹¹C-labelling method with [¹¹C]methyl triflate instead of the originally reported ruthenium-mediated ¹⁸F-deoxyfluorination. Preliminary biological evaluations using [¹¹C]EKZ-001 were also performed.</div></div><div><h3>Methods</h3><div>Carbon-11-labelling was conducted with a desmethyl precursor and [¹¹C]methyl triflate in acetone, which was selected after solvent optimisation. After the ¹¹C-labelling reaction at room temperature for 5 min, [¹¹C]EKZ-001 was purified using semipreparative high-performance liquid chromatography. The solvent of the fraction containing the product was removed by evaporation, and the resulting residue was formulated in physiological saline containing ethanol and ascorbic acid. The radioligand kinetics in the brain were assessed in normal mice by small-animal PET with and without coadministration of unlabelled EKZ-001. Metabolite analysis was also performed in the brain and plasma at 15 and 30 min after radioligand administration in normal mice. Radioligand binding in the mouse brain was evaluated by <em>in vitro</em> autoradiography and compared with HDAC6 immunostaining.</div></div><div><h3>Results</h3><div>[¹¹C]EKZ-001 was obtained in a radiochemical yield of 35.5 ± 4.2 % (decay corrected to [¹¹C]CO₂; <em>n</em> = 3), with a radiochemical purity and molar activity at the end of the synthesis of 96.0 ± 1.1 % and 111.2 ± 32.3 MBq/nmol, respectively. PET imaging in normal mice demonstrated an excellent brain uptake of [¹¹C]EKZ-001 that was reduced by coadministration of unlabelled EKZ-001. [¹¹C]EKZ-001 was stable in the mouse brain, and the proportion of [¹¹C]EKZ-001 radioactivity remained intact at 85 % even 30 min after administration. In autoradiography using mouse brain sections, [¹¹C]EKZ-001 showed specific binding in regions generally consistent with HDAC6 immunostaining.</div></div><div><h3>Conclusions</h3><div>[¹¹C]EKZ-001 can be synthesised in a conventional way with [¹¹C]methyl triflate and used as a radioligand for HDAC6 imaging in the brain.</div></div>","PeriodicalId":19363,"journal":{"name":"Nuclear medicine and biology","volume":"146 ","pages":"Article 109030"},"PeriodicalIF":3.6,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144134965","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":"Potent candidates for Targeted Alpha Therapy (TAT)","authors":"Dmitry Filosofov ,&nbsp;Ayagoz Baimukhanova ,&nbsp;Jurabek Khushvaktov ,&nbsp;Elena Kurakina ,&nbsp;Valery Radchenko","doi":"10.1016/j.nucmedbio.2025.109027","DOIUrl":"10.1016/j.nucmedbio.2025.109027","url":null,"abstract":"<div><div>Targeted Alpha Therapy (TAT) holds significant promise as a localized treatment for cancer. Encouraging clinical results from using peptides and antibodies labeled with alpha emitters to treat patients with metastatic cancers, particularly those who have not responded to other therapies, provide compelling evidence of TAT's potential. To fully realize the benefits of TAT, it is essential to carefully select appropriate radionuclides and targeting delivery systems to maximize therapeutic efficacy while minimizing nonspecific toxicity to healthy tissues. This review explores key radiochemical, radiopharmaceutical, and radiation-biological considerations for current TAT candidates, and proposes additional potential candidates, establishing a foundation and criteria for the ongoing development of TAT radiopharmaceuticals.</div></div>","PeriodicalId":19363,"journal":{"name":"Nuclear medicine and biology","volume":"146 ","pages":"Article 109027"},"PeriodicalIF":3.6,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144134964","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}