EJNMMI Radiopharmacy and Chemistry最新文献

{"title":"cGMP-compliant high-yield automated production of [18F]AlF-FAPI-74: optimization of quality control and evaluation of molar dose impact","authors":"Ward Storms,&nbsp;Sofie Celen,&nbsp;Justine Maes,&nbsp;Kim Serdons,&nbsp;Karolien Goffin,&nbsp;Tjibbe De Groot,&nbsp;Laura Trump,&nbsp;Corentin Warnier,&nbsp;Thibault Gendron,&nbsp;Romaric Gérardy,&nbsp;Koen Van Laere,&nbsp;Christophe M. Deroose,&nbsp;Janke Kleynhans,&nbsp;Frederik Cleeren","doi":"10.1186/s41181-025-00411-1","DOIUrl":"10.1186/s41181-025-00411-1","url":null,"abstract":"<div><h3>Background</h3><p>Fibroblast activation protein inhibitor (FAPI)-based positron emission tomography (PET) radiopharmaceuticals have shown promise for imaging cancer-associated fibroblasts (CAFs), a key component of the tumor microenvironment. FAPI radiopharmaceuticals offer high tumor-to-background contrast and are not influenced by hyperglycemia. Among these, [¹⁸F]AlF-FAPI-74, labeled using the Al¹⁸F-method, offers logistical advantages over ⁶⁸Ga-labeled radiopharmaceuticals, including a longer physical half-life and suitability for large-scale, centralized production. This study reports a fully automated, efficient, and GMP-compliant synthesis of [¹⁸F]AlF-FAPI-74 using the Trasis AllInOne^® platform, alongside a refined isocratic radio-HPLC method that enhances fluorine-18 recovery and impurity resolution. Additionally, the impact of molar dose on [¹⁸F]AlF-FAPI-74 biodistribution is evaluated in a preclinical model and a clinical case-study highlighting the performance of [¹⁸F]AlF-FAPI-74 produced at high apparent molar activity is provided.</p><h3>Results</h3><p>The automated GMP-compliant production was validated in three independent runs, with an average decay-corrected yield and apparent molar activity of 50 ± 10% and 1124 ± 254 GBq/µmol at the end of synthesis, respectively. Total synthesis time was 30 min. Quality control used validated analytical methods, including an optimized radio-HPLC protocol, ensuring regulatory compliance and batch consistency. [¹⁸F]AlF-FAPI-74 was produced with a radiochemical purity ≥ 95% and demonstrated excellent radiochemical stability in its final formulation for at least 10 h post-synthesis, at a concentration of 2019 MBq/mL. The in vitro binding kinetics of [¹⁸F]AlF-FAPI-74 were evaluated in a HEK293 cell line stably expressing human FAP, demonstrating rapid, specific uptake and internalization, along with high target affinity. In vivo biodistribution studies revealed a dose-dependent “molar amount effect,” with doses &gt; 30 nmol/kg yielding improved tumor-to-background ratios. This phenomenon was not observed in clinical imaging, where high molar activity supported excellent image contrast.</p><h3>Conclusions</h3><p>A robust, fully automated, and GMP-compliant production process for [¹⁸F]AlF-FAPI-74 is reported with high yield, purity, and stability, suitable for centralized production and distribution. The improved radio-HPLC method enhances quality control precision by accurately quantifying radiochemical and chemical purity. In vivo experiments confirmed fast tumor uptake of [¹⁸F]AlF-FAPI-74. While a clear mass effect on tumor-to-background ratios was observed in preclinical studies, high apparent molar activity resulted in excellent contrast in a clinical setting.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"11 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1186/s41181-025-00411-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145754864","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PDGFRß targeted positron emission tomography as a non-invasive biomarker for activated hepatic stellate cells: lasts steps before clinical translation","authors":"Chittampalli N. Yashaswini,&nbsp;Bogdan Mitran,&nbsp;Natalia Papadopoulos,&nbsp;Olivia Wegrzyniak,&nbsp;John Löfblom,&nbsp;Helena Nordström,&nbsp;Irina Velikyan,&nbsp;Ayman Abouzayed,&nbsp;Lars Johansson,&nbsp;Per Hagmar,&nbsp;Michael Wagner,&nbsp;Fredrik Y. Frejd,&nbsp;Olle Korsgren,&nbsp;Carl-Henrik Heldin,&nbsp;Scott L. Friedman,&nbsp;Olof Eriksson","doi":"10.1186/s41181-025-00410-2","DOIUrl":"10.1186/s41181-025-00410-2","url":null,"abstract":"<div><h3>Background</h3><p>Activated hepatic stellate cells (aHSCs) are the key cell population in the injured liver driving fibrogenesis. aHSCs express platelet-derived growth factor receptor beta (PDGFRß), which is absent from quiescent HSCs. PDGFRß is therefore an attractive target of PET tracers for imaging of fibrogenesis. Here, we present the pharmacological characterization of [⁶⁸Ga]Ga-DOTA-Cys-ATH001 in preparation for clinical translation and further confirm PDGFRß as a biomarker of activated HSCs in liver disease by single cell sequencing.</p><h3>Methods</h3><p>The expression of PDGFRß in subpopulations of HSCs was evaluated in scRNAseq datasets from both a mouse and human liver samples. DOTA-Cys-ATH001 was evaluated for affinity and mechanism of binding to PDGFRß. [⁶⁸Ga]Ga-DOTA-Cys-ATH001 was evaluated for binding in vitro in mouse and human liver biopsies. The in vivo stability, biodistribution, pharmacokinetics, dosimetry and microdosing toxicology were evaluated in rats and pigs.</p><h3>Results</h3><p>PDGFRß expression was specifically upregulated in activated HSCs. [⁶⁸Ga]Ga-DOTA-Cys-ATH001 could differentiate fibrotic liver from healthy liver. The binding co-localized with tissue areas positive for collagen deposition and PDGFRß immunostaining. Based on the microdosing toxicology study the no observed adverse effect level was at least 1000 µg/kg, suggesting that the intended clinical PET scan dose is safe for use. Dosimetry calculations of [⁶⁸Ga]Ga-DOTA-Cys-ATH001 predicted an effective dose in human amenable to repeated examinations.</p><h3>Conclusions</h3><p>The data presented here suggests that PDGFRβ PET imaging with [⁶⁸Ga]Ga-DOTA-Cys-ATH001 has potential for non-invasive detection of activated HSCs. Clinical translation of [⁶⁸Ga]Ga-DOTA-Cys-ATH001 is ongoing.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"10 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1186/s41181-025-00410-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145740275","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Establishing Pb-203 production from electrodeposited Tl targets at Brookhaven National Laboratory","authors":"Wilson Lin,&nbsp;Dmitri G. Medvedev,&nbsp;Cathy S. Cutler,&nbsp;Jasmine Hatcher-Lamarre","doi":"10.1186/s41181-025-00403-1","DOIUrl":"10.1186/s41181-025-00403-1","url":null,"abstract":"<div><h3>Background</h3><p>Promising developments in Pb-212 radiopharmaceutical therapies have increased demand for Pb-203 diagnostic agents. Building on previous work from various isotope production facilities, this study optimized Pb-203 production from electrodeposited Tl targets at Brookhaven National Laboratory (BNL). The additional supply of Pb-203 may help meet growing preclinical and clinical demands.</p><h3>Results</h3><p>Two Tl targets were irradiated at the Brookhaven Linac Isotope Producer facility with 30 ± 1 MeV protons, measured using previously published cross section data. Distribution coefficients for Pb Resin in acetate media were investigated for both Na⁺ and K⁺ cations, where potassium acetate was ~ 4 times more effective at stripping Pb from the Pb Resin. The Tl electrodeposition was optimized to deposit 350 mg of Tl (~ 60 mg/cm²) on Au backing in under 6 h. The proposed separation process was completed in &lt; 1.5 h and achieved &gt; 98% and 92 ± 3% recovery of Tl and Pb, respectively, with an overall Tl-Pb separation factor of 6 × 10⁵. The experimentally measured half-life of Pb-203 was 52.4 ± 0.7 h, agreeing with 51.93 ± 0.02 h reported by the National Nuclear Data Center. The radioisotopic purity of the Pb fraction at 24 h post end of bombardment (EOB) from a 24 h irradiation was 66% Pb-203, 28% Pb-201, and 6% Pb-200. Following chemical separation, the Pb-203 produced in this work (21 MBq Pb-203 EOB) achieved apparent molar activities of 10 ± 5 and 0.9 ± 0.5 GBq/µmol for [²⁰³Pb]Pb-DOTAM and [²⁰³Pb]Pb-DO3A, respectively, decay corrected to EOB. Data derived from this work suggests BNL can produce &gt; 10’s GBq Pb-203 with &gt; 99% radiochemical and radioisotopic purity from Tl-205 for worldwide distribution.</p><h3>Conclusions</h3><p>The production and separation of Pb-203 from natural Tl target material was successfully demonstrated at BNL. Existing methods were adapted and optimized for the facilities at BNL. Results from this work will guide future large-scale Pb-203 production opportunities at BNL for clinical applications.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"10 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1186/s41181-025-00403-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145712879","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aluminum-[18F]fluoride radiolabeling of triarylphosphines for cell labeling via the perfluoroaryl azide Staudinger ligation","authors":"Anisa Biti,&nbsp;Surachet Imlimthan,&nbsp;Heidi Harjunpää,&nbsp;Diana Barakhtii,&nbsp;Topias Pöllänen,&nbsp;Arina Sukhova,&nbsp;Susanne K. Wiedmer,&nbsp;Filip S. Ekholm,&nbsp;Susanna Fagerholm,&nbsp;Mirkka Sarparanta","doi":"10.1186/s41181-025-00409-9","DOIUrl":"10.1186/s41181-025-00409-9","url":null,"abstract":"<div><h3>Background</h3><p>The development of safer and more effective cell-based therapies requires robust methods for tracking cells in vivo. Positron emission tomography (PET) is a highly sensitive nuclear imaging technique capable of quantitatively tracking the in vivo fate of cells after administration. Here, we investigated a cell-labeling strategy based on metabolic glycoengineering (MGE) to introduce azides on the cell surface, followed by radiolabeling via the bioorthogonal perfluoroaryl azide (PFAA)-Staudinger reaction. We studied the metabolic incorporation of a tetraacetylated PFAA-derivatized mannosamine in Jurkat cells and evaluated whether three triarylphosphines bearing the REstrained Complexing Agent (RESCA), could be radiolabeled with aluminum-[F]fluoride (Al[¹⁸F]F) for use as bioorthogonal reagents in the PFAA-Staudinger ligation.</p><h3>Results</h3><p>Three novel triarylphosphines containing different linkers (hydrophilic ester, ethylenediamine, and cyclohexyl) between the phosphine moiety and the (+)-RESCA-chelator were synthesized and characterized. Kinetic assays showed that all compounds reacted with the PFAA-derivatized monosaccharide, exhibiting different reaction kinetics under the tested conditions. They were successfully radiolabeled with fluorine-18 under optimized mild conditions and provided key insights into the radiolabeling of small molecules bearing the RESCA-chelator. The ester derivative underwent rapid chemical decomposition while the ethylenediamine- and cyclohexyl-linked derivatives were more resistant, with the cyclohexyl analogue showing the highest stability against demetallation and/or defluorination. However, radiolabeling with Al[¹⁸F]F led to the oxidation of the phosphine moiety, with the major radiolabeled product corresponding to the oxidized form. At the same time, flow cytometry showed that the metabolic incorporation of the tetra-acetylated PFAA-derivatized mannosamine into Jurkat cells was substantially less efficient than that of the widely used tetra-acetylated <i>N</i>-azidoacetylmannosamine (Ac₄ManNAz) derivative at the equivalent concentration. Increased concentrations of the PFAA derivative compromised cell viability, which halted subsequent studies.</p><h3>Conclusions</h3><p>While the Al[¹⁸F]F radiolabeling of these (+)-RESCA-bearing small molecules offers high stability against demetallation and/or defluorination, the method cannot currently be applied to triarylphosphines due to oxidation during radiolabeling and requires further development. Among the synthesized compounds, the cyclohexyl-linked derivative exhibited the most favorable stability profile, making it a potential lead structure for future tracer development. Nevertheless, this study advanced our understanding of MGE with PFAA-derivatized monosaccharides and highlighted the need for further investigation before applying PFAA-Staudinger ligation to cell radiolabeling.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"10 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12705485/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145707007","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis and preclinical evaluation of FAP-targeting radiotracers for PET and optical imaging","authors":"Jürgen Kogler,&nbsp;Cornelius K. Donat,&nbsp;Johanna Trommer,&nbsp;Klaus Kopka,&nbsp;Sven Stadlbauer","doi":"10.1186/s41181-025-00398-9","DOIUrl":"10.1186/s41181-025-00398-9","url":null,"abstract":"<div><h3>Background</h3><p>Successful treatment of solid cancers relies on precise diagnosis, e.g. using noninvasive molecular imaging, followed by surgical removal and/or chemo/immunotherapy. Despite advances in pre-operative imaging, real-time intraoperative tools remain limited, which often results in high rates of tumor-positive margins and recurrence after tumor resection. To address this limitation, we aimed to develop multifunctional fibroblast activation protein alpha (FAP) targeting tracers for bimodal medical imaging, enabling both pre-operative noninvasive molecular imaging via positron emission tomography (PET) and optical visualization during intraoperative fluorescence-guided surgery.</p><h3>Results</h3><p>NODAGA-FAP647 and NODAGA-FAP800 targeting human FAP (hFAP) were synthesized bearing a (R)-NODAGA chelator and a fluorophore (AlexaFluor647 or IRDye800CW, respectively). Binding affinities and binding kinetics of both unlabeled and ^67/68Ga-labeled compounds were evaluated in vitro using HT1080 cells (hFAP-expressing and wild type, WT) along with respective frozen xenograft tissue sections. Using real-time binding, both compounds exhibited picomolar binding affinities to hFAP via radioactive/fluorescent detection. This was primarily driven by low dissociation rate constants in vitro. Pharmacokinetics and tumor uptake were evaluated via PET and fluorescence imaging in mice bearing xenografts from the same cells. In vivo, both compounds were rapidly distributed and accumulated in hFAP-expressing but not WT-HT1080 tumors within 10–20 min post-injection. Fluorescence imaging showed a similarly good and selective tumor uptake in the first two hours and a qualitatively visible difference compared to WT-HT1080 beyond 24 h. Both compounds were quickly cleared from normal tissue and excreted renally.</p><h3>Conclusion</h3><p>Two FAP-targeting bimodal ligands were synthesized and evaluated in vitro and in vivo, showing high specificity and selectivity, along with rapid and selective tumor accumulation. Their long tumor retention and high imaging contrast make them promising candidates for clinical translation.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"10 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12686243/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145676139","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluating methodological constraints in PET imaging of neuropeptide Y2 receptors with N-[11C]-methyl-(R)-JNJ-31020028 in brains of C57BL/6J mice","authors":"Karsten Bamminger,&nbsp;Eduardo Felipe Alves Fernandes,&nbsp;Lena Zachhuber,&nbsp;Ines Lopez-Martinez,&nbsp;Claudia Kuntner,&nbsp;Oliver Langer,&nbsp;Severin Mairinger,&nbsp;Berit Ø. Christoffersen,&nbsp;Marcus Hacker,&nbsp;Thomas Wanek","doi":"10.1186/s41181-025-00407-x","DOIUrl":"10.1186/s41181-025-00407-x","url":null,"abstract":"<div><h3>Background</h3><p>The Neuropeptide Y (NPY) system regulates mood, stress, and feeding behavior and plays a central role in neuropsychiatric and metabolic disorders. It exerts its effects primarily through a family of G-protein-coupled NPY receptors (NPYR), comprising the Y1, Y2, Y4, and Y5 subtypes. Among these, the Y2 receptor (NPY2R) has emerged as a promising imaging target through its involvement in mood regulation, anxiety, and feeding behavior. This study evaluated the in vivo performance of the selective NPY2R antagonist PET tracer <i>N</i>-[¹¹C]methyl-(<i>R</i>)-JNJ-31020028 in mice, focusing on tracer metabolism, brain uptake, and blood–brain barrier transport via P-glycoprotein (P-gp).</p><h3>Results</h3><p>In vitro, <i>N</i>-methyl-(<i>R</i>)-JNJ-31020028 showed nanomolar affinity and selectivity for the murine NPY2R with no observable interaction with mY1, mY4, and mY5. In vivo, brain percent injected dose per cc (%ID/cc), peaked within the first 5 min after injection and declined rapidly. Tariquidar pretreatment increased brain uptake more than threefold at 15 min post administration, particularly in hippocampus, thalamus, and striatum, but differences disappeared at 60 min. Radiometabolite analysis revealed rapid peripheral metabolism, and absence of intact tracer in the brain at 60 min in vehicle-treated mice. In plasma, the parent fraction was unaffected by tariquidar, while it was significantly higher in the brain with P-gp inhibition. Metabolite-corrected brain-to-plasma concentration ratios (<i>K</i>_{<i>p,brain</i>}) confirmed negligible tracer uptake without P-gp blockade.</p><h3>Conclusions</h3><p><i>N</i>-[¹¹C]methyl-(<i>R</i>)-JNJ-31020028 binds selectively to NPY2R but undergoes rapid metabolism and strong P-gp–mediated efflux at the murine blood–brain barrier. Reliable data interpretation requires early imaging and metabolite correction. For preclinical NPY2R-PET, pharmacological P-gp inhibition may be essential, and future tracers should be optimized for improved metabolic stability.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"11 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1186/s41181-025-00407-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145676129","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Assessing the radiation-induced bystander effect in radionuclide therapy using targeted radiopharmaceuticals","authors":"Rohit Sharma,&nbsp;Archana Mukherjee,&nbsp;Poonam Jagasia,&nbsp;Suman Kumar Singh","doi":"10.1186/s41181-025-00393-0","DOIUrl":"10.1186/s41181-025-00393-0","url":null,"abstract":"<div><h3>Background</h3><p>Radiation-induced biologic bystander effects (RIBBEs) where non-irradiated cells display radiation like responses are well established in the context of external beam radiotherapy. However, their presence and characteristics in radionuclide therapy have been explored in only a limited number of studies. With the growing application of radionuclide therapy, this study was designed to investigate RIBBEs using a targeting agent labeled with three different types of emitters, aiming to quantify the varying biological effects attributable to each radionuclide and to devise strategies for achieving maximum therapeutic effect.Trastuzumab antibody targeting human epidermal growth factor receptor 2 (HER2) was labeled with radionuclides of varying energy profile; Y-90 (β⁻emitter), Lu-177 (β⁻/γ-emitter), and I-125 (Auger electron emitter). The radiolabeled conjugates were characterized, and their specificity was evaluated. Studies to evaluate both direct and bystander effects in (HER2) receptor overexpressing cell lines were performed via a media transfer protocol.</p><h3>Results</h3><p>The study highlights distinct cellular responses depending on the radionuclide employed, with significant bystander induced reductions in clonogenic survival observed for all radiolabeled formulations. Notably, HER2-overexpressing SK-OV-3 and SK-BR-3 cells displayed dose-dependent variations in survival, with ⁹⁰Y and ¹⁷⁷Lu demonstrating greater bystander toxicity than ¹²⁵I. The survival fraction of recipient cells, which were exposed solely to media containing bystander factors, decreased significantly, indicating the potency of bystander factors in influencing therapeutic outcomes. Additionally, cytotoxicity assays revealed that higher doses of ⁹⁰Y and ¹⁷⁷Lu induced substantial apoptosis and necrosis, whereas ¹²⁵I exhibited lower cytotoxicity, consistent with its lower energy emission profile. Reactive oxygen species (ROS) generation assays corroborated these findings, showing elevated ROS levels in direct and donor cell groups treated with ⁹⁰Y and ¹⁷⁷Lu, while recipient cells exhibited relatively lower ROS induction.</p><h3>Conclusions</h3><p>This study elucidates the complex interplay of direct and bystander effects in targeted radionuclide therapy, demonstrating that the therapeutic efficacy and cellular response depend on the specific radionuclide and its energy profile. The findings emphasize the need for further exploration of RIBBEs to optimize radionuclide-based cancer therapies to enhance their clinical efficacy.</p><h3>Graphical abstract</h3><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"10 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1186/s41181-025-00393-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145627596","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Extending the shelf life of ⁶⁸Ge/⁶⁸Ga generators via preconcentration of [⁶⁸Ga]GaCl₃ for preclinical application","authors":"Hemantha Mallapura,&nbsp;Olof Eriksson","doi":"10.1186/s41181-025-00406-y","DOIUrl":"10.1186/s41181-025-00406-y","url":null,"abstract":"<div><h3>Background</h3><p>⁶⁸Ga-labeled tracers are increasingly important for PET imaging and as companion diagnostics with new therapeutic radiopharmaceuticals. The ⁶⁸Ge/⁶⁸Ga generator is a common source for clinical and preclinical ⁶⁸Ga-tracer production; however, its shelf life and efficiency are critical because of the high cost of generator replacement. This study assessed whether preconcentration of [⁶⁸Ga]GaCl₃ using strong cation exchange (SCX) resin can increase yield, apparent molar activity (AMA) and also extend generator shelf-life for preclinical applications.</p><h3>Results</h3><p>A ⁶⁸Ge/⁶⁸Ga generator (1.8 GBq at purchase, 14–18 months old) was used. Direct elution involved elution of [⁶⁸Ga]GaCl₃ in 0.1 M HCl, followed by addition to a DOTA-conjugated affibody in acetate buffer (pH 4.6). Preconcentration involved trapping [⁶⁸Ga]GaCl₃ on a SCX (Chromafix PS-H⁺) cartridge, rinsing, and eluting with 0.12 M HCl in 5 M NaCl (300–500 µL), followed by radiolabeling. Radiolabeling was performed at 75–80 °C for 15 min, the products were purified using a NAP-5 column, and the purity was assessed by high-performance liquid chromatography (HPLC). The SCX cartridge trapping efficiency was &gt; 99%, with a elution efficiency of 95.2 ± 1.2% (n = 8). For direct elution, the decay-corrected radiochemical yield (RCYdc) was 78.7 ± 1.5% (n = 3), the AMA was 5.6 ± 0.4 MBq/nmol, and the radiochemical purity (RCP) was 95.3 ± 0.6%. For preconcentration, RCY_dc was 69.0 ± 10.0% (n = 3), AMA was 12.6 ± 2.1 MBq/nmol, and RCP was 95.7 ± 3.0%.</p><h3>Conclusions</h3><p>The preconcentration technique doubled the product yield and AMA, and extended the shelf life of the generator by 9–12 months for preclinical applications. Preconcentration of [⁶⁸Ga]GaCl₃ using SCX resin is a robust, cost-effective method for maximizing ⁶⁸Ga recovery and increasing the radiotracer yield and AMA, especially with older generators. This approach extends generator shelf-life, supports sustained preclinical research, and reduces radioactive waste and operational costs.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"10 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12669415/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145601657","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Optimization of the radiosynthesis of the PSMA-targeting drugs [177Lu]Lu-P17-087 and [177Lu]Lu-P17-088 on the MiniLu™ automated module","authors":"David Alexoff,&nbsp;Karl Ploessl,&nbsp;Ruiyue Zhao,&nbsp;Linlin Li,&nbsp;Dohyun Kim,&nbsp;Lin Zhu,&nbsp;Hank Kung","doi":"10.1186/s41181-025-00400-4","DOIUrl":"10.1186/s41181-025-00400-4","url":null,"abstract":"<div><h3>Background</h3><p>There is a renewed interest in radioligand therapy for cancer treatment since the approval of Lu-177 vipivotide tetraxetan (PSMA-617) by regulators in Europe and the United States for metastatic castrate resistant prostate cancer (mCRPC) patients. Recent expansion of indications for vipivotide tetraxetan in mCRPC by the FDA promises to increase demand for this class of radioligand therapy. The development of new targeted radioligands for mCRPC that improve binding specificity and increase radiation dose delivered to tumors is an active research space. [¹⁷⁷Lu]Lu-P17-087 and [¹⁷⁷Lu]Lu-P17-088 are new prostate specific membrane antigen (PSMA) targeted drugs under clinical investigation in China. Heretofore the preparation of these investigational drugs has been carried out manually. This report introduces a new cassette-based, radiosynthesis platform named MiniLu™ and describes the optimization and automation of the preparation of [¹⁷⁷Lu]Lu-P17-087 and [¹⁷⁷Lu]Lu-P17-088 for clinical use.</p><h3>Results</h3><p>Radiolabeling of [¹⁷⁷Lu]Lu-P17-087 was optimized for pH, time, temperature and ligand concentration using 0.2 – 13 MBq of Lu-177 (&gt; 740 GBq/mg) and MiniLu™. &gt; 99% labeling yield measured by thin layer chromatography (TLC) was achieved with a pH = 5, 50–110 °C, 10 min, 3:1 mol ratio ligand: Lu-177; ligand mass &gt; 3 nmole in 0.5 mL reaction solution. Quantitative labeling was confirmed using these conditions (80 °C) in simulations of clinical production doses of Lu-177 (7.4 GBq; &gt; 3000 GBq/mg) by adding cold [^natLu]LuCl₃ (14 nmoles). [¹⁷⁷Lu]Lu-P17-088 labeling yield was &gt; 99% under the identical simulation conditions. A final product yield (activity in dose vial / starting Lu-177 activity) of ~ 95% was achieved after formulation with L-ascorbate and gentisic acid (15 mL) and sterile filtration using MiniLu™ and the simulated high activity conditions for both compounds. Final optimized concentrations for automated dose preparation were 62 µM (0.6 mL) and 70 µM (0.6 mL) for [¹⁷⁷Lu]Lu-P17-087 and [¹⁷⁷Lu]Lu-P17-088, respectively. Over 100 independent automated MiniLu™ runs were completed successfully.</p><h3>Conclusions</h3><p>[¹⁷⁷Lu]Lu-P17-087 and [¹⁷⁷Lu]Lu-P17-088 doses can be produced in high yield (95%) and purity (99%) using MiniLu™. Optimized, automated methods using MiniLu™ will facilitate further clinical investigations using [¹⁷⁷Lu]Lu-P17-087 and [¹⁷⁷Lu]Lu-P17-088 by standardizing preparation and reducing radiation exposure to radiochemists.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"10 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12623512/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145538289","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Improving GRPR-targeting peptides for radiotheranostics application: insights from chelator modifications and α-methyl-L tryptophan substitution","authors":"Karim Obeid,&nbsp;Ekaterina Bezverkhniaia,&nbsp;Vladimir Tolmachev,&nbsp;Anna Orlova,&nbsp;Panagiotis Kanellopoulos","doi":"10.1186/s41181-025-00402-2","DOIUrl":"10.1186/s41181-025-00402-2","url":null,"abstract":"<div><h3>Background</h3><p>Targeting the gastrin-releasing peptide receptor (GRPR) is a promising approach for radionuclide therapy in prostate and breast cancers. GRPR-targeting peptides often have limited metabolic stability, which can compromise their clinical efficacy due to rapid degradation in the bloodstream, leading to reduced tumor uptake. We previously reported the GRPR-targeting peptide AU-RM26-M2 (DOTAGA-PEG₂-Pip-[Sar¹¹]RM26), which demonstrated promising pharmacokinetics in GRPR-expressing xenografts. In this study, we aimed to enhance the metabolic stability and targeting properties of AU-RM26-M2 by incorporating α-methyl-L-tryptophan (MetTrp) at position 8 in the pharmacophore, and to investigate the influence of chelator choice (DOTAGA vs. DOTA) for labeling with Lu-177, a β-emitting therapeutic nuclide.</p><h3>Results</h3><p>Therefore, we designed two peptides: PKB2 (DOTAGA-PEG₂-Pip-[MetTrp⁸, Sar¹¹]RM26) and PKB3 (DOTA-PEG₂-Pip-[MetTrp⁸, Sar¹¹]RM26). For comparison, we also evaluated the DOTA-bearing analogue of AU-RM26-M2, PKB1 (DOTA-PEG₂-Pip-[Sar¹¹]RM26). PKB1, PKB2, and PKB3 were labeled with Lu-177, achieving high radiochemical yields (&gt; 97%) and purities (&gt; 93%). In PC-3 cells, [¹⁷⁷Lu]Lu-PKB1, [¹⁷⁷Lu]Lu-PKB2, and [¹⁷⁷Lu]Lu-PKB3 showed affinity in the sub-nanomolar range and high specificity for GRPR, with a slow internalization rate. The radiopeptides with MetTrp⁸ modification had high metabolic stability against peptidases in vivo. In PC-3 xenografts, [¹⁷⁷Lu]Lu-PKB2 and [¹⁷⁷Lu]Lu-PKB3 demonstrated rapid background clearance and high GRPR-mediated tumor activity uptake at 2 h pi, exceeding activity uptake in the kidneys. Activity uptake in the tumor was highly retained at 24 h pi.</p><h3>Conclusions</h3><p>This study led to the development of two metabolically stable GRPR-targeting radiopeptides, [¹⁷⁷Lu]Lu-PKB2 and [¹⁷⁷Lu]Lu-PKB3, with a high potential for targeted radionuclide therapy.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"10 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ejnmmipharmchem.springeropen.com/counter/pdf/10.1186/s41181-025-00402-2","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145501403","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}