EJNMMI Radiopharmacy and Chemistry最新文献

{"title":"Radiosynthesis and preclinical evaluation of a 68Ga-labeled tetrahydroisoquinoline-based ligand for PET imaging of C-X-C chemokine receptor type 4 in an animal model of glioblastoma","authors":"Piyapan Suwattananuruk,&nbsp;Sukanya Yaset,&nbsp;Chanisa Chotipanich,&nbsp;Angel Moldes-Anaya,&nbsp;Rune Sundset,&nbsp;Rodrigo Berzaghi,&nbsp;Stine Figenschau,&nbsp;Sandra Claes,&nbsp;Dominique Schols,&nbsp;Pornchai Rojsitthisak,&nbsp;Mathias Kranz,&nbsp;Opa Vajragupta","doi":"10.1186/s41181-024-00290-y","DOIUrl":"10.1186/s41181-024-00290-y","url":null,"abstract":"<div><h3>Background</h3><p>This study aimed to develop a novel positron emission tomography (PET) tracer, [⁶⁸Ga]Ga-TD-01, for CXCR4 imaging. To achieve this goal, the molecular scaffold of TIQ15 was tuned by conjugation with the DOTA chelator to make it suitable for ⁶⁸Ga radiolabeling.</p><h3>Methods</h3><p>A bifunctional chelator was prepared by conjugating the amine group of TIQ15 with <i>p-</i>NCS-Bz-DOTA, yielding TD-01, with a high yield (68.92%). TD-01 was then radiolabeled with ⁶⁸Ga using 0.1 M ammonium acetate at 60 °C for 10 min. A 1-h dynamic small animal PET/MRI study of the labeled compound in GL261-luc2 tumor-bearing mice was performed, and brain tumor uptake was assessed. Blocking studies involved pre-administration of TIQ15 (10 mg/kg) 10 min before the PET procedure started.</p><h3>Results</h3><p>[⁶⁸Ga]Ga-TD-01 exhibited a radiochemical yield (RCY) of 36.33 ± 1.50% (EOS), with a radiochemical purity &gt; 99% and a molar activity of 55.79 ± 1.96 GBq/µmol (EOS). The radiotracer showed in vitro stability in PBS and human plasma for over 4 h. Biodistribution studies in healthy animals revealed favorable kinetics for subsequent PET pharmacokinetic modeling with low uptake in the brain and moderate uptake in lungs, intestines and spleen. Elimination could be assigned to a renal-hepatic pathway as showed by high uptake in kidneys, liver, and urinary bladder. Importantly, [⁶⁸Ga]Ga-TD-01 uptake in glioblastoma (GBM)-bearing mice significantly decreased upon competition with TIQ15, with a baseline tumor-to-background ratios &gt; 2.5 (20 min p.i.), indicating high specificity.</p><h3>Conclusion</h3><p>The newly developed CXCR4 PET tracer, [⁶⁸Ga]Ga-TD-01, exhibited a high binding inhibition for CXCR4, excellent in vitro stability, and favorable pharmacokinetics, suggesting that the compound is a promising candidate for full in vivo characterization of CXCR4 expression in GBM, with potential for further development as a tool in cancer diagnosis.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"9 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ejnmmipharmchem.springeropen.com/counter/pdf/10.1186/s41181-024-00290-y","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142003260","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":"Scalability study on [133La]LaCl3 production with a focus on potential clinical applications","authors":"Santiago Andrés Brühlmann,&nbsp;Martin Walther,&nbsp;Magdalena Kerstin Blei,&nbsp;Constantin Mamat,&nbsp;Klaus Kopka,&nbsp;Robert Freudenberg,&nbsp;Martin Kreller","doi":"10.1186/s41181-024-00292-w","DOIUrl":"10.1186/s41181-024-00292-w","url":null,"abstract":"<div><h3>Background</h3><p>In recent years, targeted alpha therapy has gained importance in the clinics, and in particular, the alpha-emitter ²²⁵Ac plays a fundamental role in this clinical development. Nevertheless, depending on the chelating system no real diagnostic alternative has been established which shares similar chemical properties with this alpha-emitting radionuclide. In fact, the race to launch a diagnostic radionuclide to form a matched pair with ²²⁵Ac is still open, and ¹³³La features attractive radiation properties to claim this place. However, in order to enable its translation into clinical use, upscaling of the production of this PET radionuclide is needed.</p><h3>Results</h3><p>A study on optimal irradiation parameters, separation conditions and an exhaustive product characterization was carried out. In this framework, a proton irradiation of 2 h, 60 µA and 18.7 MeV produced ¹³³La activities of up to 10.7 GBq at end of bombardment. In addition, the performance of four different chromatographic resins were tested and two optimized purification methods presented, taking approximately 20 min with a ¹³³La recovery efficiencies of over 98%, decay corrected. High radionuclide purity and apparent molar activity was proved, of over 99.5% and 120 GBq/µmol, respectively, at end of purification. Furthermore, quantitative complexation of PSMA-617 and mcp-M-PSMA were obtained with molar activities up to 80 GBq/µmol. In addition, both ¹³³La-radioconjugates offered high stability in serum, of over (98.5 ± 0.3)% and (99.20 ± 0.08)%, respectively, for up to 24 h. A first dosimetry estimation was also performed and it was calculated that an ¹³³La application for imaging with between 350 and 750 MBq would only have an effective dose of 2.1–4.4 mSv, which is comparable to that of ¹⁸F and ⁶⁸Ga based radiopharmaceuticals.</p><h3>Conclusions</h3><p>In this article we present an overarching study on ¹³³La production, from the radiation parameters optimization to a clinical dose estimation. Lanthanum-133 activities in the GBq range could be produced, formulated as [¹³³La]LaCl₃ with high quality regarding radiolabeling and radionuclide purity. We believe that increasing the ¹³³La availability will further promote the development of radiopharmaceuticals based on macropa or other chelators suitable for ²²⁵Ac.</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":"9 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ejnmmipharmchem.springeropen.com/counter/pdf/10.1186/s41181-024-00292-w","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141987193","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":"109Pd/109mAg in-vivo generator in the form of nanoparticles for combined β- - Auger electron therapy of hepatocellular carcinoma","authors":"Nasrin Abbasi Gharibkandi,&nbsp;Kamil Wawrowicz,&nbsp;Rafał Walczak,&nbsp;Agnieszka Majkowska-Pilip,&nbsp;Mateusz Wierzbicki,&nbsp;Aleksander Bilewicz","doi":"10.1186/s41181-024-00293-9","DOIUrl":"10.1186/s41181-024-00293-9","url":null,"abstract":"<div><h3>Background</h3><p>Convenient therapeutic protocols for hepatocellular carcinoma (HCC) are often ineffective due to late diagnosis and high tumor heterogeneity, leading to poor long-term outcomes. However, recently performed studies suggest that using nanostructures in liver cancer treatment may improve therapeutic effects. Inorganic nanoparticles represent a unique material that tend to accumulate in the liver when introduced in-vivo. Typically, this is a major drawback that prevents the therapeutic use of nanoparticles in medicine. However, in HCC tumours, this may be advantageous because nanoparticles may accumulate in the target organ, where the leaky vasculature of HCC causes their accumulation in tumour cells <i>via</i> the EPR effect. On the other hand, recent studies have shown that combining low- and high-LET radiation emitted from the same radionuclide, such as ¹⁶¹Tb, can increase the effectiveness of radionuclide therapy. Therefore, to improve the efficacy of radionuclide therapy for hepatocellular carcinoma, we suggest utilizing radioactive palladium nanoparticles in the form of ¹⁰⁹Pd/^109mAg in-vivo generator that simultaneously emits β⁻ particles and Auger electrons.</p><h3>Results</h3><p>Palladium nanoparticles with a size of 5 nm were synthesized using ¹⁰⁹Pd produced through neutron irradiation of natural palladium or enriched ¹⁰⁸Pd. Unlike the ¹⁰⁹Pd-cyclam complex, where the daughter radionuclide diffuses away from the molecules, ^109mAg remains within the nanoparticles after the decay of ¹⁰⁹Pd. In vitro cell studies using radioactive ¹⁰⁹Pd nanoparticles revealed that the nanoparticles accumulated inside cells, reaching around 50% total uptake. The ¹⁰⁹Pd-PEG nanoparticles exhibited high cytotoxicity, even at low levels of radioactivity (6.25 MBq/mL), resulting in almost complete cell death at 25 MBq/mL. This cytotoxic effect was significantly greater than that of PdNPs labeled with β⁻ (¹³¹I) and Auger electron emitters (¹²⁵I). The metabolic viability of HCC cells was found to be correlated with cell DNA DSBs. Also, successful radioconjugate anticancer activity was observed in three-dimensional tumor spheroids, resulting in a significant treatment response.</p><h3>Conclusion</h3><p>The results indicate that nanoparticles labeled with ¹⁰⁹Pd can be effectively used for combined β⁻ - Auger electron-targeted radionuclide therapy of HCC. Due to the decay of both components (β⁻ and Auger electrons), the ¹⁰⁹Pd/^109mAg in-vivo generator presents a unique potential in this field.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"9 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ejnmmipharmchem.springeropen.com/counter/pdf/10.1186/s41181-024-00293-9","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141970330","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":"Development of caspase-3-selective activity-based probes for PET imaging of apoptosis","authors":"Louis Lauwerys,&nbsp;Lucas Beroske,&nbsp;Angelo Solania,&nbsp;Christel Vangestel,&nbsp;Alan Miranda,&nbsp;Nele Van Giel,&nbsp;Karuna Adhikari,&nbsp;Anne-Marie Lambeir,&nbsp;Leonie wyffels,&nbsp;Dennis Wolan,&nbsp;Pieter Van der Veken,&nbsp;Filipe Elvas","doi":"10.1186/s41181-024-00291-x","DOIUrl":"10.1186/s41181-024-00291-x","url":null,"abstract":"<div><h3>Background</h3><p>The cysteine-aspartic acid protease caspase-3 is recognized as the main executioner of apoptosis in cells responding to specific extrinsic and intrinsic stimuli. Caspase-3 represents an interesting biomarker to evaluate treatment response, as many cancer therapies exert their effect by inducing tumour cell death. Previously developed caspase-3 PET tracers were unable to reach routine clinical use due to low tumour uptake or lack of target selectivity, which are two important requirements for effective treatment response evaluation in cancer patients. Therefore, the goal of this study was to develop and preclinically evaluate novel caspase-3-selective activity-based probes (ABPs) for apoptosis imaging.</p><h3>Results</h3><p>A library of caspase-3-selective ABPs was developed for tumour apoptosis detection. In a first attempt, the inhibitor Ac-DW3-KE (Ac-3Pal-Asp-βhLeu-Phe-Asp-KE) was ¹⁸F-labelled on the N-terminus to generate a radiotracer that was incapable of adequately detecting an increase in apoptosis in vivo. The inability to effectively detect active caspase-3 in vivo was likely attributable to slow binding, as demonstrated with in vitro inhibition kinetics. Hence, a second generation of caspase-3 selective ABPs was developed based on the Ac-ATS010-KE (Ac-3Pal-Asp-Phe(F₅)-Phe-Asp-KE) with greatly improved binding kinetics over Ac-DW3-KE. Our probes based on Ac-ATS010-KE were made by modifying the N-terminus with 6 different linkers. All the linker modifications had limited effect on the binding kinetics, target selectivity, and pharmacokinetic profile in healthy mice. In an in vitro apoptosis model, the least hydrophilic tracer [¹⁸F]MICA-316 showed an increased uptake in apoptotic cells in comparison to the control group. Finally, [¹⁸F]MICA-316 was tested in an in vivo colorectal cancer model, where it showed a limited tumour uptake and was unable to discriminate treated tumours from the untreated group, despite demonstrating that the radiotracer was able to bind caspase-3 in complex mixtures in vitro. In contrast, the phosphatidylethanolamine (PE)-binding radiotracer [^99mTc]Tc-duramycin was able to recognize the increased cell death in the disease model, making it the best performing treatment response assessment tracer developed thus far.</p><h3>Conclusions</h3><p>In conclusion, a novel library of caspase-3-binding PET tracers retaining similar binding kinetics as the original inhibitor was developed. The most promising tracer, [¹⁸F]MICA-316, showed an increase uptake in an in vitro apoptosis model and was able to selectively bind caspase-3 in apoptotic tumour cells. In order to distinguish therapy-responsive from non-responsive tumours, the next generation of caspase-3-selective ABPs will be developed with higher tumour accumulation and in vivo stability.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"9 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11310375/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141905421","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":"Cyclotron production of manganese-52: a promising avenue for multimodal PET/MRI imaging","authors":"Francesca Porto,&nbsp;Sara Cisternino,&nbsp;Emiliano Cazzola,&nbsp;Giorgia Speltri,&nbsp;Liliana Mou,&nbsp;Alessandra Boschi,&nbsp;Lorenza Marvelli,&nbsp;Giovanni Di Domenico,&nbsp;Antonella Pagnoni,&nbsp;Lucia De Dominicis,&nbsp;Irene Calliari,&nbsp;Claudio Gennari,&nbsp;Licia Uccelli,&nbsp;Gaia Pupillo,&nbsp;Giancarlo Gorgoni,&nbsp;Juan Esposito,&nbsp;Petra Martini","doi":"10.1186/s41181-024-00288-6","DOIUrl":"10.1186/s41181-024-00288-6","url":null,"abstract":"<div><h3>Background</h3><p>The integration of positron emission tomography (PET) and magnetic resonance imaging (MRI) holds promise for advancing diagnostic imaging capabilities. The METRICS project aims to develop cyclotron-driven production of ⁵²Mn for PET/MRI imaging.</p><h3>Results</h3><p>Using the ⁵²Cr(p,n)⁵²Mn reaction, we designed chromium metal targets via Spark Plasma Sintering and developed a separation procedure for isolating ⁵²Mn. Labeling tests were conducted with traditional chelators (i.e. S-2-(4-Isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane tetraacetic acid) and the 1.4-dioxa-8-azaspiro[4.5]decane-8- carbodithioate ligand to produce radioactive complexes suitable for PET/MRI applications. Our methodology yielded high-quality ⁵²Mn suitable for PET radiopharmaceuticals and PET/MRI imaging. Preliminary studies on phantom imaging using microPET and clinical MRI demonstrated the efficacy of our approach.</p><h3>Conclusions</h3><p>The developed technology offers a promising avenue for producing ⁵²Mn and enhancing PET/MRI imaging capabilities. Further in vivo investigations are warranted to evaluate the potential advantages of this hybrid imaging technique.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"9 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11297007/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141873849","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":"The development of 177Lu-DOTA-CC-PSMA following a unified “Click Chemistry” protocol of synthesizing metal nuclide-conjugated radiopharmaceuticals","authors":"Xiaobei Zheng,&nbsp;Shuai Xue,&nbsp;Zhongqi Zhao,&nbsp;Shuxin Jin,&nbsp;Shuhua He,&nbsp;Lina Jia,&nbsp;Zheng Li,&nbsp;Christian Vanhove,&nbsp;Filip De Vos,&nbsp;Zijun Kuang,&nbsp;Tiantian Wang,&nbsp;Sara Neyt,&nbsp;Lan Zhang,&nbsp;Xiao Li","doi":"10.1186/s41181-024-00287-7","DOIUrl":"10.1186/s41181-024-00287-7","url":null,"abstract":"<div><h3>Background</h3><p>Currently, the synthesis pathway of metal nuclide-labeled radiopharmaceuticals is mainly divided into two steps: first, connecting the chelator with the target molecule, and second, labeling the metal nuclide to the chelator. However, the second step of the reaction to label the metal nuclide requires high temperature (90–100 °C), which tends to denature and inactivate the target molecule, leading to loss of biological activities, especially the targeting ability. A feasible solution may be the click chemistry labeling method, which consists of reacting a metal nuclide with a chelating agent to generate an intermediate and then synthesizing a radiopharmaceutical agent via the click chemistry intermediate and the target molecule-alkyne compound. In this study, through the click chemistry of ¹⁷⁷Lu-DOTA-N₃ with prostate-specific membrane antigen (PSMA)-alkyne compound, ¹⁷⁷Lu-labeled PSMA-targeted molecular probe was synthesized and evaluated for its potential to be cleared from the bloodstream and rapidly distributed to tissues and organs, achieving a high target/non-target ratio. ¹⁷⁷Lu-PSMA-617 was utilized as an analogue for comparison in terms of synthesizing efficiency and PSMA-targeting ability.</p><h3>Results</h3><p>A novel ¹⁷⁷Lu-labeled PSMA radioligand was successfully synthesized through the click chemistry of ¹⁷⁷Lu-DOTA-N₃ with PSMA-alkyne compound, and abbreviated as ¹⁷⁷Lu-DOTA-CC-PSMA, achieving a radiochemical yield of 77.07% ± 0.03% (<i>n</i> = 6) and a radiochemical purity of 97.62% ± 1.49% (<i>n</i> = 6) when purified by SepPak C18 column. Notably, ¹⁷⁷Lu-DOTA-CC-PSMA was characterized as a hydrophilic compound that exhibited stability at room temperature and commendable pharmacokinetic properties, such as the superior uptake (19.75 ± 3.02%ID/g at 0.5 h) and retention (9.14 ± 3.16%ID/g at 24 h) within xenografts of 22Rv1 tumor-bearing mice. SPECT/CT imaging indicated that radioactivity in both kidneys and bladder was essentially eliminated after 24 h, while ¹⁷⁷Lu-DOTA-CC-PSMA was further enriched and retained in PSMA-expressing tumors, resulting in the high target/non-target ratio.</p><h3>Conclusion</h3><p>This study demonstrated the potential of click chemistry to unify the synthesis of metal radiopharmaceuticals, and ¹⁷⁷Lu-DOTA-CC-PSMA was found for rapid clearance and appropriate chemical stability as a PSMA-targeted radioligand.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"9 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11291776/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141854368","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":"In vitro and in vivo analyses of eFAP: a novel FAP-targeting small molecule for radionuclide theranostics and other oncological interventions","authors":"Circe D. van der Heide,&nbsp;Hanyue Ma,&nbsp;Mark W.H. Hoorens,&nbsp;Joana D. Campeiro,&nbsp;Debra C. Stuurman,&nbsp;Corrina M.A. de Ridder,&nbsp;Yann Seimbille,&nbsp;Simone U. Dalm","doi":"10.1186/s41181-024-00283-x","DOIUrl":"10.1186/s41181-024-00283-x","url":null,"abstract":"<div><h3>Background</h3><p>Fibroblast activation protein (FAP), a transmembrane serine protease overexpressed by cancer-associated fibroblasts in the tumor stroma, is an interesting biomarker for targeted radionuclide theranostics. FAP-targeting radiotracers have demonstrated to be superior to [¹⁸F]FDG PET/CT in various solid cancers. However, these radiotracers have suboptimal tumor retention for targeted radionuclide therapy (TRT). We aimed to develop a novel FAP-targeting pharmacophore with improved pharmacokinetics by introducing a substitution at the 8-position of (4-quinolinoyl)-glycyl-2-cyanopyrrolidine, which allows for conjugation of a chelator, dye, or other payloads.</p><h3>Results</h3><p>Here we showed the synthesis of DOTA-conjugated eFAP-6 and sulfo-Cyanine5-conjugated eFAP-7. After chemical characterization, the uptake and specificity of both tracers were determined on FAP-expressing cells. In vitro, [¹¹¹In]In-eFAP-6 demonstrated a superior affinity and a more rapid, although slightly lower, peak uptake than gold standard [¹¹¹In]In-FAPI-46. Confocal microscopy demonstrated a quick FAP-mediated internalization of eFAP-7. Studies with HT1080-huFAP xenografted mice confirmed a more rapid uptake of [¹⁷⁷Lu]Lu-eFAP-6 vs. [¹⁷⁷Lu]Lu-FAPI-46. However, tumor retention at 24 h post injection of [¹⁷⁷Lu]Lu-eFAP-6 was lower than that of [¹⁷⁷Lu]Lu-FAPI-46, hereby currently limiting its use for TRT.</p><h3>Conclusion</h3><p>The superior affinity and faster tumor accumulation of eFAP-6 over FAPI-46 makes it a suitable compound for radionuclide imaging. After further optimization, the eFAP series has great potential for various oncological interventions, including fluorescent-guided surgery and effective targeted radionuclide theranostics.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"9 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11286609/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141786981","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":"Generic semi-automated radiofluorination strategy for single domain antibodies: [18F]FB-labelled single domain antibodies for PET imaging of fibroblast activation protein-α or folate receptor-α overexpression in cancer","authors":"Herlinde Dierick,&nbsp;Laurent Navarro,&nbsp;Hannelore Ceuppens,&nbsp;Thomas Ertveldt,&nbsp;Ana Rita Pombo Antunes,&nbsp;Marleen Keyaerts,&nbsp;Nick Devoogdt,&nbsp;Karine Breckpot,&nbsp;Matthias D’Huyvetter,&nbsp;Tony Lahoutte,&nbsp;Vicky Caveliers,&nbsp;Jessica Bridoux","doi":"10.1186/s41181-024-00286-8","DOIUrl":"10.1186/s41181-024-00286-8","url":null,"abstract":"<div><h3>Background</h3><p>Radiofluorination of single domain antibodies (sdAbs) via <i>N</i>-succinimidyl-4-[¹⁸F]fluorobenzoate ([¹⁸F]SFB) has shown to be a promising strategy in the development of sdAb-based PET tracers. While automation of the prosthetic group (PG) [¹⁸F]SFB production, has been successfully reported, no practical method for large scale sdAb labelling has been reported. Therefore, we optimized and automated the PG production, enabling a subsequently efficient manual conjugation reaction to an anti-fibroblast activation protein (FAP)-α sdAb (4AH29) and an anti-folate receptor (FR)-α sdAb (2BD42). Both the alpha isoform of FAP and the FR are established tumour markers. FAP-α is known to be overexpressed mainly by cancer-associated fibroblasts in breast, ovarian, and other cancers, while its expression in normal tissues is low or undetectable. FR-α has an elevated expression in epithelial cancers, such as ovarian, brain and lung cancers. Non-invasive imaging techniques, such as PET-imaging, using tracers targeting specific tumour markers can provide molecular information over both the tumour and its environment, which aides in the diagnosis, therapy selection and assessment of the cancer treatment.</p><h3>Results</h3><p>[¹⁸F]SFB was synthesized using a fully automated three-step, one-pot reaction. The total procedure time was 54 min and results in [¹⁸F]SFB with a RCP &gt; 90% and a RCY d.c. of 44 ± 4% (n = 13). The manual conjugation reaction after purification produced [¹⁸F]FB-sdAbs with a RCP &gt; 95%, an end of synthesis activity &gt; 600 MBq and an apparent molar activity &gt; 10 GBq/µmol. Overall RCY d.c., corrected to the trapping of [¹⁸F]F⁻ on the QMA, were 9% (n = 1) and 5 ± 2% (n = 3) for [¹⁸F]FB-2BD42 and [¹⁸F]FB-4AH29, respectively.</p><h3>Conclusion</h3><p>[¹⁸F]SFB synthesis was successfully automated and upscaled on a Trasis AllInOne module. The anti-hFAP-α and anti-hFR-α sdAbs were radiofluorinated, yielding similar RCYs d.c. and RCPs, showing the potential of this method as a generic radiofluorination strategy for sdAbs. The radiofluorinated sdAbs showed a favourable biodistribution pattern and are attractive for further characterization as new PET tracers for FAP-α and FR-α imaging.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"9 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2024-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11269545/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141756419","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":"Process validation and preclinical development of a new PET cerebral blood flow tracer [11C]MMP for initial clinical trials","authors":"Jun Toyohara,&nbsp;Tetsuro Tago,&nbsp;Muneyuki Sakata","doi":"10.1186/s41181-024-00285-9","DOIUrl":"10.1186/s41181-024-00285-9","url":null,"abstract":"<div><h3>Background</h3><p>2-deoxy-2-[¹⁸F]fluoro-D-glucose ([¹⁸F]FDG) is commonly used for diagnosis of dementia because brain glucose metabolism reflects neuronal activity. However, as [¹⁸F]FDG is an analogue of glucose, accumulation of tracer in the brain is affected by plasma glucose levels. In contrast, cerebral blood flow (CBF) tracers are theoretically unaffected by plasma glucose levels and are therefore expected to be useful alternatives for the diagnosis of dementia in patients with diabetes. The techniques currently used for CBF imaging using single photon emission computed tomography (SPECT) and [¹⁵O]H₂O positron emission tomography (PET), but these are limited by their insufficient resolution and sensitivity for regional brain imaging, especially in patients with brain atrophy. <i>N</i>-isopropyl-4-[¹¹C]methylamphetamine ([¹¹C]MMP) is a possible CBF tracer with high resolution and sensitivity that exhibits comparable performance to that of [¹⁵O]H₂O in conscious monkey brains. We performed process validation of the radiosynthesis and preclinical development of [¹¹C]MMP prior to clinical translation.</p><h3>Results</h3><p>The decay-corrected yields of [¹¹C]MMP at the end of synthesis were 41.4 ± 6.5%, with 99.7 ± 0.3% radiochemical purity, and 192.3 ± 22.5 MBq/nmol molar activity. All process validation batches complied with the product specifications. The acute toxicity of MMP was evaluated at a dose of 3.55 mg/kg body weight, which is 10,000 times the potential maximum clinical dose of [¹¹C]MMP. The acute toxicity of [¹¹C]MMP injection at 150 or 200 times, to administer a postulated dose of 740 MBq of [¹¹C]MMP, was also evaluated after the decay-out of ¹¹C. No acute toxicity of MMP and [¹¹C]MMP injection was found. No mutagenic activity was observed for MMP. The effective dose calculated according to the Medical Internal Radiation Dose (MIRD) method was 5.4 µSv/MBq, and the maximum absorbed dose to the bladder wall was 57.6 µGy/MBq. MMP, a derivative of phenylalkylamine, showed binding to the sigma receptor, but had approximately 1/100 of the affinity of existing sigma receptor imaging agents. The affinity for other brain neuroreceptors was low.</p><h3>Conclusions</h3><p>[¹¹C]MMP shows acceptable pharmacological safety at the dose required for adequate PET imaging. The potential risk associated with [¹¹C]MMP PET imaging is well within the acceptable dose limit.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"9 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2024-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11266321/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141747106","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":"Preclinical evaluation of CXCR4 peptides for targeted radionuclide therapy in glioblastoma","authors":"Anthony Waked,&nbsp;Melissa Crabbé,&nbsp;Virginie Neirinckx,&nbsp;Sunay Rodriguez Pérez,&nbsp;Jasmien Wellens,&nbsp;Bernard Rogister,&nbsp;M. Abderrafi Benotmane,&nbsp;Koen Vermeulen","doi":"10.1186/s41181-024-00282-y","DOIUrl":"10.1186/s41181-024-00282-y","url":null,"abstract":"<div><h3>Background</h3><p>Glioblastoma (GBM), is the most fatal form of brain cancer, with a high tendency for recurrence despite combined treatments including surgery, radiotherapy, and chemotherapy with temozolomide. The C-X-C chemokine receptor 4 (CXCR4) plays an important role in tumour radioresistance and recurrence, and is considered as an interesting GBM target. TRT holds untapped potential for GBM treatment, with CXCR4-TRT being a promising strategy for recurrent GBM treatment. Our study focuses on the preclinical assessment of different ¹⁷⁷Lu-labelled CXCR4-targeting peptides, CTCE-9908, DV1-K-DV3, and POL3026 for GBM treatment and exploring some of the radiobiological mechanisms underlying these therapies.</p><h3>Results</h3><p>All three DOTA-conjugated peptides could be radiolabelled with ¹⁷⁷Lu with &gt; 95% radiochemical yield. Binding studies show high specific binding of [¹⁷⁷Lu]Lu-DOTA-POL3026 to U87-CXCR4 + cells, with 42% of the added activity binding to the membrane at 1 nM, and 6.5% internalised into the cells. In the presence of the heterologous CXCR4 blocking agent, AMD11070, membrane binding was reduced by 95%, a result confirmed by quantitative in vitro autoradiography of orthotopic GBM xenograft sections. An activity-dependent decrease in cell viability was observed for [¹⁷⁷Lu]Lu-DOTA-DV1-K-DV3 and [¹⁷⁷Lu]Lu-DOTA-POL3026, along with a slight increase in the induction of apoptotic markers. Additionally, the expression of γH2AX increased in a time-and activity-dependent manner. Ex vivo biodistribution studies with [¹⁷⁷Lu]Lu-DOTA-POL3026 show uptake in the tumour reaching a SUV of 1.9 at 24 h post-injection, with higher uptake in the kidneys, lungs, spleen, and liver. Dosimetry estimations show an absorbed dose of 0.93 Gy/MBq in the tumour. A blocking study with AMD11070 showed a 38% reduction in tumour uptake, with no significant reduction observed in µSPECT imaging. Although no brain uptake was observed in the ex vivo biodistribution study, autoradiography on U87-CXCR4 + tumour inoculated mouse brain slices shows non-specific binding in the brain, next to high specific binding to the tumour.</p><h3>Conclusions</h3><p>In conclusion, we compared different ¹⁷⁷Lu-radiolabelled CXCR4-targeting peptides for their binding potential in GBM, and demonstrated their varied cytotoxic action against GBM cells in vitro, with POL3026 being the most promising, causing considerable DNA damage. Though the peptide’s systemic biodistribution remains to be improved, our data demonstrate the potential of [¹⁷⁷Lu]Lu-DOTA-POL3026 for CXCR4-TRT in the context of GBM.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"9 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ejnmmipharmchem.springeropen.com/counter/pdf/10.1186/s41181-024-00282-y","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141615517","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}