Pub Date : 2025-06-02DOI: 10.1186/s41181-025-00351-w
S. Spreckelmeyer, J. Dasilva, C. Decristoforo, R. H. Mach, J. Passchier, G. Carlucci, M. Al Qahtani, A. Duatti, B. T. Cornelissen, J. Engle, A. Denkova, J. J. M. A. Hendrikx, Y. Seimbille, X. Yang, H. Jia, M-R. Zhang, M. Yang, L. Perk, P. Caravan, P. Laverman, Z. Cheng, C. Hoehr, T. Sakr, J. R. Zeevaart
{"title":"Correction: Highlight selection of radiochemistry and radiopharmacy developments by editorial board","authors":"S. Spreckelmeyer, J. Dasilva, C. Decristoforo, R. H. Mach, J. Passchier, G. Carlucci, M. Al Qahtani, A. Duatti, B. T. Cornelissen, J. Engle, A. Denkova, J. J. M. A. Hendrikx, Y. Seimbille, X. Yang, H. Jia, M-R. Zhang, M. Yang, L. Perk, P. Caravan, P. Laverman, Z. Cheng, C. Hoehr, T. Sakr, J. R. Zeevaart","doi":"10.1186/s41181-025-00351-w","DOIUrl":"10.1186/s41181-025-00351-w","url":null,"abstract":"","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"10 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12130380/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144197959","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}
Pub Date : 2025-05-30DOI: 10.1186/s41181-025-00347-6
Anzhelika Vorobyeva, Moeen-ud Din, Alexey Schulga, Elena Konovalova, Ayman Abouzayed, Olga Bragina, Ruonan Li, Torbjörn Gräslund, Sergey M. Deyev, Maryam Oroujeni
Background
Epithelial cell adhesion molecule (EpCAM) is a transmembrane glycoprotein, which is overexpressed in several types of malignancies. Designed ankyrin repeat protein (DARPin) Ec1 is a 19 kDa engineered scaffold protein that binds with high affinity to EpCAM. Radiolabelled Ec1 might be used as a companion diagnostic for the selection of patients for personalized therapy. This study aimed to investigate the influence of different radiometal-chelator complexes on the biodistribution and imaging contrast of 68Ga-labelled Ec1. To investigate this, two macrocyclic chelators, 1,4,7-triazacyclononane-N,N,N-triacetic acid (NOTA) and 1-(1,3-carboxypropyl)-1,4,7-triazacyclononane-4,7-diacetic acid (NODAGA) were conjugated to the C-terminus of the Ec1. The previously developed DARPin Ec1 conjugated to 1,4,7,10-tetraazacylododecane-1,4,7,10-tetraacetic acid (DOTA) was used as a comparator.
Results
All Ec1 variants were successfully labelled with 68Ga. The use of NOTA and NODAGA provided twice higher radiochemical yield and improved label stability compared to DOTA. All labelled Ec1 variants bound to the EpCAM-expressing cells with nanomolar affinity and preserved targeting specificity in vitro and in vivo. Biodistribution studies in mice bearing EpCAM-expressing SKOV-3 xenografts showed that [68Ga]Ga-Ec1-NOTA had lower uptake in most normal organs while maintaining tumor uptake. Among all variants, [68Ga]Ga-Ec1-NOTA showed the lowest liver uptake, with no significant differences in tumor uptake. Additionally, [68Ga]Ga-Ec1-NOTA provided the highest tumor-to-blood ratio compared to [68Ga]Ga-Ec1-DOTA and [68Ga]Ga-Ec1-NODAGA.
Conclusion
[68Ga]Ga-Ec1-NOTA is the preferred radioconjugate for PET imaging of EpCAM expression.
{"title":"Selection of the optimal chelator for labeling of DARPin Ec1 with gallium-68 for PET imaging of EpCAM expression","authors":"Anzhelika Vorobyeva, Moeen-ud Din, Alexey Schulga, Elena Konovalova, Ayman Abouzayed, Olga Bragina, Ruonan Li, Torbjörn Gräslund, Sergey M. Deyev, Maryam Oroujeni","doi":"10.1186/s41181-025-00347-6","DOIUrl":"10.1186/s41181-025-00347-6","url":null,"abstract":"<div><h3>Background</h3><p>Epithelial cell adhesion molecule (EpCAM) is a transmembrane glycoprotein, which is overexpressed in several types of malignancies. Designed ankyrin repeat protein (DARPin) Ec1 is a 19 kDa engineered scaffold protein that binds with high affinity to EpCAM. Radiolabelled Ec1 might be used as a companion diagnostic for the selection of patients for personalized therapy. This study aimed to investigate the influence of different radiometal-chelator complexes on the biodistribution and imaging contrast of <sup>68</sup>Ga-labelled Ec1. To investigate this, two macrocyclic chelators, 1,4,7-triazacyclononane-N,N,N-triacetic acid (NOTA) and 1-(1,3-carboxypropyl)-1,4,7-triazacyclononane-4,7-diacetic acid (NODAGA) were conjugated to the C-terminus of the Ec1. The previously developed DARPin Ec1 conjugated to 1,4,7,10-tetraazacylododecane-1,4,7,10-tetraacetic acid (DOTA) was used as a comparator.</p><h3>Results</h3><p>All Ec1 variants were successfully labelled with <sup>68</sup>Ga. The use of NOTA and NODAGA provided twice higher radiochemical yield and improved label stability compared to DOTA. All labelled Ec1 variants bound to the EpCAM-expressing cells with nanomolar affinity and preserved targeting specificity in vitro and in vivo. Biodistribution studies in mice bearing EpCAM-expressing SKOV-3 xenografts showed that [<sup>68</sup>Ga]Ga-Ec1-NOTA had lower uptake in most normal organs while maintaining tumor uptake. Among all variants, [<sup>68</sup>Ga]Ga-Ec1-NOTA showed the lowest liver uptake, with no significant differences in tumor uptake. Additionally, [<sup>68</sup>Ga]Ga-Ec1-NOTA provided the highest tumor-to-blood ratio compared to [<sup>68</sup>Ga]Ga-Ec1-DOTA and [<sup>68</sup>Ga]Ga-Ec1-NODAGA.</p><h3>Conclusion</h3><p>[<sup>68</sup>Ga]Ga-Ec1-NOTA is the preferred radioconjugate for PET imaging of EpCAM expression.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"10 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12125460/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144186174","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}
Pub Date : 2025-05-30DOI: 10.1186/s41181-025-00346-7
Fahimeh Bayat
Background
Radiolabeling is a technique that involves attaching radioactive isotopes to molecules, allowing for their tracking and analysis in biological systems. Radiolabeled d-glucose and its derivatives have a very prominent role in exploring metabolic pathways, the enzymatic system, and measuring the flow of the metabolites through biochemical reactions, as accumulation or deficiency of metabolites occurs along with metabolic disorders. Glucose as the main source of energy in the body is involved in different metabolic pathways like glycolysis, pentose phosphate pathway, and tricarboxylic acid cycle. Various derivatives of glucose are labeled at different positions by 14C and 3H. The aim of this review is to summarize some of the most significant aspects of the use of different radiolabeled d-glucose, 2-deoxy-d-glucose, and methyl-α-d-glucopyranoside.
Main body
This review focuses on the application of radiolabeled glucose derivatives in studying glucose transport systems, metabolic pathways, enzyme activity, and glucose utilization across various tissues. It highlights their role in understanding disease mechanisms in diabetes, cancer, heart failure, and metabolic disorders, and the impact of pharmacological agents and environmental pollutants.
Conclusion
In conclusion, radiolabeled glucose derivatives are invaluable tools for studying glucose metabolism across various tissues and organs. They provide critical insights into metabolic dysfunctions, disease mechanisms, and therapeutic interventions, aiding in the development of targeted treatments for conditions like diabetes, cancer, and cardiovascular diseases.
背景：放射性标记是一种将放射性同位素附着到分子上的技术，允许在生物系统中对其进行跟踪和分析。放射性标记的d -葡萄糖及其衍生物在探索代谢途径、酶系统和通过生化反应测量代谢物流量方面具有非常突出的作用，因为代谢物的积累或缺乏伴随着代谢紊乱而发生。葡萄糖作为机体的主要能量来源，参与糖酵解、戊糖磷酸途径、三羧酸循环等多种代谢途径。葡萄糖的各种衍生物在不同位置用14C和3H标记。本文综述了不同放射性标记的d -葡萄糖、2-脱氧d -葡萄糖和甲基-α- d -葡萄糖苷的一些最重要的方面。正文：本文综述了放射性标记葡萄糖衍生物在研究葡萄糖转运系统、代谢途径、酶活性和葡萄糖在不同组织中的利用方面的应用。它强调了它们在理解糖尿病、癌症、心力衰竭和代谢紊乱的疾病机制以及药理药物和环境污染物的影响方面的作用。结论：放射性标记葡萄糖衍生物是研究不同组织和器官中葡萄糖代谢的宝贵工具。它们为代谢功能障碍、疾病机制和治疗干预提供了重要见解，有助于开发针对糖尿病、癌症和心血管疾病等疾病的靶向治疗方法。
{"title":"d-Glucose and its derivatives labeled with radioactive carbon and hydrogen: key tools for investigating biological processes and molecular mechanisms","authors":"Fahimeh Bayat","doi":"10.1186/s41181-025-00346-7","DOIUrl":"10.1186/s41181-025-00346-7","url":null,"abstract":"<div><h3>Background</h3><p>Radiolabeling is a technique that involves attaching radioactive isotopes to molecules, allowing for their tracking and analysis in biological systems. Radiolabeled <span>d</span>-glucose and its derivatives have a very prominent role in exploring metabolic pathways, the enzymatic system, and measuring the flow of the metabolites through biochemical reactions, as accumulation or deficiency of metabolites occurs along with metabolic disorders. Glucose as the main source of energy in the body is involved in different metabolic pathways like glycolysis, pentose phosphate pathway, and tricarboxylic acid cycle. Various derivatives of glucose are labeled at different positions by <sup>14</sup>C and <sup>3</sup>H. The aim of this review is to summarize some of the most significant aspects of the use of different radiolabeled <span>d</span>-glucose, 2-deoxy-<span>d</span>-glucose, and methyl-<i>α</i>-<span>d</span>-glucopyranoside.</p><h3>Main body</h3><p>This review focuses on the application of radiolabeled glucose derivatives in studying glucose transport systems, metabolic pathways, enzyme activity, and glucose utilization across various tissues. It highlights their role in understanding disease mechanisms in diabetes, cancer, heart failure, and metabolic disorders, and the impact of pharmacological agents and environmental pollutants.</p><h3>Conclusion</h3><p>In conclusion, radiolabeled glucose derivatives are invaluable tools for studying glucose metabolism across various tissues and organs. They provide critical insights into metabolic dysfunctions, disease mechanisms, and therapeutic interventions, aiding in the development of targeted treatments for conditions like diabetes, cancer, and cardiovascular diseases.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"10 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12125467/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144186173","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}
Pub Date : 2025-05-19DOI: 10.1186/s41181-025-00349-4
Subhani M. Okarvi, Yousef Maliki
Background
Simultaneous targeting of RGD and FA receptors on breast carcinoma could improve the diagnostic outcome of breast cancer patients. In this study, we have designed and synthesized an FA-RGD heteromeric targeting vector, with both RGD and FA motifs, in one single molecule for positron emission tomography (PET) diagnostic imaging of breast carcinoma.
Results
Aoa-FA-RGD peptide conjugate was radiolabeled efficiently with [18F]FDG, resulting in high labeling efficiency (≥ 85%). The in vitro stability of the radiotracer in human plasma was found to be high. The Aoa-FA-RGD peptide conjugate showed the nanomolar affinity (≤ 51 nM) to the TNBC MDA-MB-231 cell line. In the MDA-MB-231 xenografts model, [18F]FDG-Aoa-FA-RGD peptide conjugate exhibited efficient clearance from the blood and excretion predominantly by the renal pathway (~ 56% ID), possibly due to its hydrophilic nature. A rapid accumulation of 3.30% ID/g in the TNBC MDA-MB-231 tumors was observed at 45 min p.i. Whereas a low accumulation of radioactivity was seen in the normal organs, including the heart, lungs, liver, stomach, spleen, intestines, and kidneys (< 4% ID/g). The receptor specificity of the radiotracer was confirmed by the receptor-blocking assay. A rapid and efficient tumor targeting, together with the favorable pharmacokinetics, highlights the tumor-targeting potential of the radiofluroconjugate. Furthermore, PET imaging provided sufficient visualization of MDA-MB-231 tumors in mice.
Conclusions
Our findings suggest that the [18F]FDG-labeled FA-RGD peptide conjugate can be a useful agent for the efficient targeting of TNBC cells. This study suggests the potential of this innovative heteromeric targeting agent for rapid and efficient targeting of tumors and merits further advancement.
背景RGD和FA受体同时靶向乳腺癌可改善乳腺癌患者的诊断结果。在这项研究中，我们设计并合成了一个FA-RGD异质靶向载体，同时具有RGD和FA基序，用于乳腺癌正电子发射断层扫描（PET）诊断成像。结果[18F]FDG对saoa - fa - rgd肽偶联物进行了有效的放射性标记，标记效率高（≥85%）。该放射性示踪剂在人血浆中的体外稳定性较高。Aoa-FA-RGD肽偶联物对TNBC MDA-MB-231细胞系具有纳米摩尔亲和力（≤51 nM）。在MDA-MB-231异种移植物模型中，[18F]FDG-Aoa-FA-RGD肽偶联物表现出有效的血液清除和主要通过肾途径排泄（~ 56% ID），可能是由于其亲水性。在45 min p.i时，TNBC MDA-MB-231肿瘤的放射性迅速积累为3.30% ID/g。而在正常器官，包括心、肺、肝、胃、脾、肠和肾中，放射性积累较低（4% ID/g）。受体阻断试验证实了放射性示踪剂的受体特异性。快速有效的肿瘤靶向，加上良好的药代动力学，突出了放射性氟偶联物的肿瘤靶向潜力。此外，PET成像提供了小鼠MDA-MB-231肿瘤的充分可视化。结论[18F] fdg标记的FA-RGD肽偶联物可能是一种有效靶向TNBC细胞的有效药物。这项研究表明，这种创新的异源靶向药物具有快速有效靶向肿瘤的潜力，值得进一步发展。
{"title":"Preparation and preclinical evaluation of 18F-labeled folate-RGD peptide conjugate for PET imaging of triple-negative breast carcinoma","authors":"Subhani M. Okarvi, Yousef Maliki","doi":"10.1186/s41181-025-00349-4","DOIUrl":"10.1186/s41181-025-00349-4","url":null,"abstract":"<div><h3>Background</h3><p>Simultaneous targeting of RGD and FA receptors on breast carcinoma could improve the diagnostic outcome of breast cancer patients. In this study, we have designed and synthesized an FA-RGD heteromeric targeting vector, with both RGD and FA motifs, in one single molecule for positron emission tomography (PET) diagnostic imaging of breast carcinoma.</p><h3>Results</h3><p>Aoa-FA-RGD peptide conjugate was radiolabeled efficiently with [<sup>18</sup>F]FDG, resulting in high labeling efficiency (≥ 85%). The in vitro stability of the radiotracer in human plasma was found to be high. The Aoa-FA-RGD peptide conjugate showed the nanomolar affinity (≤ 51 nM) to the TNBC MDA-MB-231 cell line. In the MDA-MB-231 xenografts model, [<sup>18</sup>F]FDG-Aoa-FA-RGD peptide conjugate exhibited efficient clearance from the blood and excretion predominantly by the renal pathway (~ 56% ID), possibly due to its hydrophilic nature. A rapid accumulation of 3.30% ID/g in the TNBC MDA-MB-231 tumors was observed at 45 min p.i. Whereas a low accumulation of radioactivity was seen in the normal organs, including the heart, lungs, liver, stomach, spleen, intestines, and kidneys (< 4% ID/g). The receptor specificity of the radiotracer was confirmed by the receptor-blocking assay. A rapid and efficient tumor targeting, together with the favorable pharmacokinetics, highlights the tumor-targeting potential of the radiofluroconjugate. Furthermore, PET imaging provided sufficient visualization of MDA-MB-231 tumors in mice.</p><h3>Conclusions</h3><p>Our findings suggest that the [<sup>18</sup>F]FDG-labeled FA-RGD peptide conjugate can be a useful agent for the efficient targeting of TNBC cells. This study suggests the potential of this innovative heteromeric targeting agent for rapid and efficient targeting of tumors and merits further advancement.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"10 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ejnmmipharmchem.springeropen.com/counter/pdf/10.1186/s41181-025-00349-4","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144090973","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}
Pub Date : 2025-05-17DOI: 10.1186/s41181-025-00342-x
Julia Greiser, Beatrice Engert, Roman Föll, Robert Klopfleisch, Rebecca Steens, Marion Hecht, Martin Freesmeyer
Background
N,1,4-Tri(4-ethoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine (TEoS-DAZA), a novel radiopharmaceutical precursor for a liver-specific 68Ga-based diagnostic radiopharmaceutical, was tested for toxicity in rats to ensure its safe applicability and to fulfil the preclinical requirements in preparation of a clinical study. The study was performed according to EMA draft Guideline on the non-clinical requirements for radiopharmaceuticals, as well as to the so-called microdosing approach of the ICH guideline M3 (R2).
Results
This randomized study was conducted using Wistar rats. The test item was administered intravenously at three different dose levels, the vehicle solution was administered to a separate group as control. Toxicity assessment included a 24 h observation period in three dose groups, and a 14-day recovery period in the high dose group. Animals were monitored regarding clinical behaviour, bodyweight, food and water consumption, additionally undergoing modified IRWIN, grip-strength and beam-walking tests. Following euthanisation, extensive haematological and clinical biochemical parameters were analysed. Necropsy and histopathology were performed. There was no evidence to any test-item related adversities at any dose level. No delayed effects were identified in any animal at the end of the recovery phase. Some small, albeit significant changes in haematology and clinical biochemistry could not be related to the test item administration. The NOAEL of TEoS-DAZA was determined at 1.4 mg/kg bodyweight.
Conclusions
Administration of a thousandfold clinical dose of TEoS-DAZA in rats did not cause any observable adverse events. An injectable solution of [68Ga]Ga-TEoS-DAZA containing 100 µg of the precursor is safe for clinical application to humans from the pharmacological point of view. Subsequent dosimetry studies need to be undertaken to reveal any radiation related toxicity.
{"title":"Toxicity study of TEoS-DAZA, a chemical precursor for functional liver imaging with PET/CT","authors":"Julia Greiser, Beatrice Engert, Roman Föll, Robert Klopfleisch, Rebecca Steens, Marion Hecht, Martin Freesmeyer","doi":"10.1186/s41181-025-00342-x","DOIUrl":"10.1186/s41181-025-00342-x","url":null,"abstract":"<div><h3>Background</h3><p><i>N</i>,1,4-Tri(4-ethoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine (TEoS-DAZA), a novel radiopharmaceutical precursor for a liver-specific <sup>68</sup>Ga-based diagnostic radiopharmaceutical, was tested for toxicity in rats to ensure its safe applicability and to fulfil the preclinical requirements in preparation of a clinical study. The study was performed according to EMA draft Guideline on the non-clinical requirements for radiopharmaceuticals, as well as to the so-called microdosing approach of the ICH guideline M3 (R2).</p><h3>Results</h3><p>This randomized study was conducted using Wistar rats. The test item was administered intravenously at three different dose levels, the vehicle solution was administered to a separate group as control. Toxicity assessment included a 24 h observation period in three dose groups, and a 14-day recovery period in the high dose group. Animals were monitored regarding clinical behaviour, bodyweight, food and water consumption, additionally undergoing modified IRWIN, grip-strength and beam-walking tests. Following euthanisation, extensive haematological and clinical biochemical parameters were analysed. Necropsy and histopathology were performed. There was no evidence to any test-item related adversities at any dose level. No delayed effects were identified in any animal at the end of the recovery phase. Some small, albeit significant changes in haematology and clinical biochemistry could not be related to the test item administration. The NOAEL of TEoS-DAZA was determined at 1.4 mg/kg bodyweight.</p><h3>Conclusions</h3><p>Administration of a thousandfold clinical dose of TEoS-DAZA in rats did not cause any observable adverse events. An injectable solution of [<sup>68</sup>Ga]Ga-TEoS-DAZA containing 100 µg of the precursor is safe for clinical application to humans from the pharmacological point of view. Subsequent dosimetry studies need to be undertaken to reveal any radiation related toxicity.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"10 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ejnmmipharmchem.springeropen.com/counter/pdf/10.1186/s41181-025-00342-x","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144073555","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}
Pub Date : 2025-05-13DOI: 10.1186/s41181-025-00341-y
Arnaud Deschavannes, Kazuma Terashi, Marie Piquemal, Catherine Rioufol, Anthony Clotagatide
Background
The increasing use of [⁶⁸Ga]Ga-based radiopharmaceuticals in PET imaging, requires efficient quality control procedures. The standard r-TLC method for verifying [⁶⁸Ga]Ga-EDOTREOTIDE (Somakit-TOC®) radiochemical purity (RCP) is time-consuming, creating workflow challenges in radiopharmacies. This study evaluates an optimized r-TLC method with a reduced migration distance (4 cm vs. 9 cm) to improve efficiency while maintaining analytical reliability. Tests for specificity, accuracy and robustness were performed using ITLC-SG – Acetate and ITLC-SG – Citrate systems. Additionally, migration time was analyzed to evaluate whether the alternative method could offer added benefits.
Results
The mean Rs for ITLC-SG – Acetate at 4 cm was 2.43 ± 0.28, while for ITLC-SG – Citrate with added [⁶⁸Ga]GaCl₃ was 5.58 ± 0.23, both exceeding the threshold of 1.5. The mean RCP at 4 cm was 98.90% ± 0.25%, and 99.21% ± 0.19% at 9 cm, with [⁶⁸Ga]Ga-uncomplexed remaining within acceptable limits. No [⁶⁸Ga]GaCl₃ was detected. The coefficient of variation (CV) for RCP between methods was < 2% (0.22%). Operator-based analysis yielded a mean Rs of 3.95 ± 0.06 (CV = 1.52%) and a mean [⁶⁸Ga]Ga-EDOTREOTIDE percentage of 99.60% ± 0.03% (CV = 0.03%). Migration times were significantly reduced with the alternative method (85% reduction).
Conclusion
Shortening the migration distance in r-TLC did not compromise specificity, accuracy or robustness while significantly reducing analysis time. The proposed method enhances PET radiopharmaceutical workflows, allowing faster patient dose preparation without quality loss. This approach could be investigated to other [68Ga]Ga-labeled compounds, supporting improved clinical and research applications in nuclear medicine.
{"title":"Optimization of radiochemical purity assessment for [68Ga]Ga-EDOTREOTIDE (Somakit-TOC®): a shortened r-TLC method for improved PET radiopharmaceutical workflow","authors":"Arnaud Deschavannes, Kazuma Terashi, Marie Piquemal, Catherine Rioufol, Anthony Clotagatide","doi":"10.1186/s41181-025-00341-y","DOIUrl":"10.1186/s41181-025-00341-y","url":null,"abstract":"<div><h3>Background</h3><p>The increasing use of [⁶⁸Ga]Ga-based radiopharmaceuticals in PET imaging, requires efficient quality control procedures. The standard r-TLC method for verifying [⁶⁸Ga]Ga-EDOTREOTIDE (Somakit-TOC<sup>®</sup>) radiochemical purity (RCP) is time-consuming, creating workflow challenges in radiopharmacies. This study evaluates an optimized r-TLC method with a reduced migration distance (4 cm vs. 9 cm) to improve efficiency while maintaining analytical reliability. Tests for specificity, accuracy and robustness were performed using ITLC-SG – Acetate and ITLC-SG – Citrate systems. Additionally, migration time was analyzed to evaluate whether the alternative method could offer added benefits.</p><h3>Results</h3><p>The mean Rs for ITLC-SG – Acetate at 4 cm was 2.43 ± 0.28, while for ITLC-SG – Citrate with added [⁶⁸Ga]GaCl₃ was 5.58 ± 0.23, both exceeding the threshold of 1.5. The mean RCP at 4 cm was 98.90% ± 0.25%, and 99.21% ± 0.19% at 9 cm, with [⁶⁸Ga]Ga-uncomplexed remaining within acceptable limits. No [⁶⁸Ga]GaCl₃ was detected. The coefficient of variation (CV) for RCP between methods was < 2% (0.22%). Operator-based analysis yielded a mean Rs of 3.95 ± 0.06 (CV = 1.52%) and a mean [⁶⁸Ga]Ga-EDOTREOTIDE percentage of 99.60% ± 0.03% (CV = 0.03%). Migration times were significantly reduced with the alternative method (85% reduction).</p><h3>Conclusion</h3><p>Shortening the migration distance in r-TLC did not compromise specificity, accuracy or robustness while significantly reducing analysis time. The proposed method enhances PET radiopharmaceutical workflows, allowing faster patient dose preparation without quality loss. This approach could be investigated to other [<sup>68</sup>Ga]Ga-labeled compounds, supporting improved clinical and research applications in nuclear medicine.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"10 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ejnmmipharmchem.springeropen.com/counter/pdf/10.1186/s41181-025-00341-y","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143944179","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}
Pub Date : 2025-05-13DOI: 10.1186/s41181-025-00345-8
Xiyan Rui, Yuzhou Ding, Nailian Zhang, Xinran Zhao, Chie Seki, Tomoteru Yamasaki, Masayuki Fujinaga, Ming-Rong Zhang, Jun Qian, Bin Ji, Rong Zhou
Background
Colony-stimulating factor 1 receptor (CSF1R) is a promising imaging biomarker for neuroinflammation and tumor-associated macrophages. However, existing positron emission tomography (PET) tracers for CSF1R imaging often suffer from limited specificity or sensitivity.
Results
We have performed 11C-labeled radiosynthesis of compound FJRD (3-((2-amino-5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)ethynyl)-N-(4-methoxyphenyl)-4-methylbenzamide), which exhibits excellent affinity for CSF1R, and evaluated its in vivo and in vitro binding properties. PET images of [11C]FJRD show low brain uptake and specific binding in the living organs, except the kidneys in both normal mice and rats. In vitro autoradiographs demonstrate high levels of specific binding in all investigated organs, including the brain, spleen, liver, kidneys and lungs, when self-blocking was used. The addition of CPPC partially blocked in vitro [11C]FJRD binding in these organs, with blocking effects ranging from 9 to 67%. In contrast, the other two CSF1R inhibitors, GW2580 and BLZ945, showed minimal blocking effects, suggesting unignorable off-target binding in these organs. Furthermore, specific binding of [11C]CPPC and [11C]GW2580 was faint in the mouse organs, with [11C]CPPC demonstrating detectable binding only in the spleen.
Conclusions
These results suggest that [11C]FJRD is a potential CSF1R-PET tracer for more sensitive detection of CSF1R, compared to [11C]CPPC and [11C]GW2580. However, the high level off-target binding necessitates further improvements in specificity for CSF1R imaging.
{"title":"Evaluation of in vivo and in vitro binding property of a novel candidate PET tracer for CSF1R imaging and comparison with two currently-used CSF1R-PET tracers","authors":"Xiyan Rui, Yuzhou Ding, Nailian Zhang, Xinran Zhao, Chie Seki, Tomoteru Yamasaki, Masayuki Fujinaga, Ming-Rong Zhang, Jun Qian, Bin Ji, Rong Zhou","doi":"10.1186/s41181-025-00345-8","DOIUrl":"10.1186/s41181-025-00345-8","url":null,"abstract":"<div><h3>Background</h3><p>Colony-stimulating factor 1 receptor (CSF1R) is a promising imaging biomarker for neuroinflammation and tumor-associated macrophages. However, existing positron emission tomography (PET) tracers for CSF1R imaging often suffer from limited specificity or sensitivity.</p><h3>Results</h3><p>We have performed <sup>11</sup>C-labeled radiosynthesis of compound FJRD (3-((2-amino-5-(1-methyl-1<i>H</i>-pyrazol-4-yl)pyridin-3-yl)ethynyl)-<i>N</i>-(4-methoxyphenyl)-4-methylbenzamide), which exhibits excellent affinity for CSF1R, and evaluated its in vivo and in vitro binding properties. PET images of [<sup>11</sup>C]FJRD show low brain uptake and specific binding in the living organs, except the kidneys in both normal mice and rats. In vitro autoradiographs demonstrate high levels of specific binding in all investigated organs, including the brain, spleen, liver, kidneys and lungs, when self-blocking was used. The addition of CPPC partially blocked in vitro [<sup>11</sup>C]FJRD binding in these organs, with blocking effects ranging from 9 to 67%. In contrast, the other two CSF1R inhibitors, GW2580 and BLZ945, showed minimal blocking effects, suggesting unignorable off-target binding in these organs. Furthermore, specific binding of [<sup>11</sup>C]CPPC and [<sup>11</sup>C]GW2580 was faint in the mouse organs, with [<sup>11</sup>C]CPPC demonstrating detectable binding only in the spleen.</p><h3>Conclusions</h3><p>These results suggest that [<sup>11</sup>C]FJRD is a potential CSF1R-PET tracer for more sensitive detection of CSF1R, compared to [<sup>11</sup>C]CPPC and [<sup>11</sup>C]GW2580. However, the high level off-target binding necessitates further improvements in specificity for CSF1R imaging.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"10 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ejnmmipharmchem.springeropen.com/counter/pdf/10.1186/s41181-025-00345-8","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143944178","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}
Pub Date : 2025-05-04DOI: 10.1186/s41181-025-00343-w
Ammar Alfteimi, Yi Zhao, Ulf Lützen, Alexander Helm, Michael Jüptner, Maaz Zuhayra
Background
[18F]Fallypride PET has been used to study D2/3 receptor occupancy and density in neuropsychiatric disorders including Huntington’s disease (HD) and aging in humans. Nevertheless, the various synthetic methods including those provided by commercial synthesizers for [18F]fallypride exhibit a disadvantage concerning the necessity of using a HPLC purification step, which causes difficulties in the automation, leads to long synthesis times and moderate yields. Therefore utilizing the purification step by SPE cartridges is considered highly desirable for future commercialization of radiopharmaceutical cassettes. In our lab we have developed a simplified reliable automatic Radiosynthesis of [18F]fallypride by using SPE cartridges for the purification step without the need of HPLC.
Results
A simplified Radiosynthesis of [18F]fallypride has been developed without the use of HPLC for both a commercial cassette based synthesis system (AllinOne (AiO) system, Trasis, Belgium) and a research synthesis module with fixed tubing (RNplus, Synthra, Germany). The cleaning step involves a serial combination of several SPE cartridges. The synthesis time was shortened by 44% compared to synthesis using HPLC. At the same time the not decay corrected yield increases from 44 to 59% by using TBAHCO3 as phase transfer catalysts and from 17 to 31% for the synthesis with K2CO3/Kryptofix-[2.2.2] compared to synthesis using HPLC. The Radiochemical purity was always > 98% and all quality control parameters (e.g. sterility, endotoxin, stability and Radiochemical purity) conformed with requirements of the European Pharmacopoeia.
Conclusions
A GMP compliant automatic synthesis of [18F]fallypride including purification using simple solid phase extraction cartridges instead of HPLC was developed and evaluated. The implementation of the simplified synthesis in both used commercial modules allows efficient and reproducible Radiosynthesis of [18F]fallypride and leads to short synthesis times and high radiochemical yields with high radiochemical purity.
{"title":"GMP compliant simplified fast and high yielding automated synthesis of [18F]fallypride without the need of HPLC purification","authors":"Ammar Alfteimi, Yi Zhao, Ulf Lützen, Alexander Helm, Michael Jüptner, Maaz Zuhayra","doi":"10.1186/s41181-025-00343-w","DOIUrl":"10.1186/s41181-025-00343-w","url":null,"abstract":"<div><h3>Background</h3><p>[<sup>18</sup>F]Fallypride PET has been used to study D2/3 receptor occupancy and density in neuropsychiatric disorders including Huntington’s disease (HD) and aging in humans. Nevertheless, the various synthetic methods including those provided by commercial synthesizers for [<sup>18</sup>F]fallypride exhibit a disadvantage concerning the necessity of using a HPLC purification step, which causes difficulties in the automation, leads to long synthesis times and moderate yields. Therefore utilizing the purification step by SPE cartridges is considered highly desirable for future commercialization of radiopharmaceutical cassettes. In our lab we have developed a simplified reliable automatic Radiosynthesis of [<sup>18</sup>F]fallypride by using SPE cartridges for the purification step without the need of HPLC.</p><h3>Results</h3><p>A simplified Radiosynthesis of [<sup>18</sup>F]fallypride has been developed without the use of HPLC for both a commercial cassette based synthesis system (AllinOne (AiO) system, Trasis, Belgium) and a research synthesis module with fixed tubing (RNplus, Synthra, Germany). The cleaning step involves a serial combination of several SPE cartridges. The synthesis time was shortened by 44% compared to synthesis using HPLC. At the same time the not decay corrected yield increases from 44 to 59% by using TBAHCO<sub>3</sub> as phase transfer catalysts and from 17 to 31% for the synthesis with K<sub>2</sub>CO<sub>3</sub>/Kryptofix-[2.2.2] compared to synthesis using HPLC. The Radiochemical purity was always > 98% and all quality control parameters (e.g. sterility, endotoxin, stability and Radiochemical purity) conformed with requirements of the European Pharmacopoeia.</p><h3>Conclusions</h3><p>A GMP compliant automatic synthesis of [<sup>18</sup>F]fallypride including purification using simple solid phase extraction cartridges instead of HPLC was developed and evaluated. The implementation of the simplified synthesis in both used commercial modules allows efficient and reproducible Radiosynthesis of [<sup>18</sup>F]fallypride and leads to short synthesis times and high radiochemical yields with high radiochemical purity.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"10 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ejnmmipharmchem.springeropen.com/counter/pdf/10.1186/s41181-025-00343-w","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143904751","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}
Pub Date : 2025-05-04DOI: 10.1186/s41181-025-00344-9
Michela Aurilio, Aureliana Esposito, Monica Buonanno, Anna Morisco, Costantina Maisto, Stefania Scala, Secondo Lastoria
Background
Targeted Alpha Therapy shows very promising clinical results in a cancer treatment and it should be comparable or better than chemotherapy and β-radionuclide therapy, in terms of efficacy and toxicity. The use of α-emission offers advantages over β-emission due to the high linear energy transfer and the limited range in tissue. Actinium-225 is an α-emitter with a half-life of 9.92 days, which is an appropriate half-life for convenient treatment. Actinium-225 is introduced to tumor-targeting vectors through its complexation by a chelating moiety. On this basis, the aim of this study is to develop an [225Ac]Ac-PSMA 617 production method, to assess the efficiency and reliability of the radiosynthesis as a support for establish a clinical routine production for metastatic castration resistant prostate cancer treatment.
Results
different radiolabeling conditions and different reaction times have been used and compared. The best radiochemical yields (> 95%) were obtained when the peptide was dissolved in water and it was used at quantity of 100 µg in gentisic buffer, without stabilizing agent. The reaction was conducted at 97 °C and no significant change in labeling yield was observed when the time reaction increased. This condition ensures an adequate stability at 24 h around 90%.
Conclusions
the radiolabeling method employed in our experiments has demonstrated consistent reproducibility, enabling us to produce a radiopharmaceutical that meets pharmaceutical-grade standards. Greater difficulties occurred in defining the optimal procedures for quality controls, due to the unique physical properties of actinium. Efforts were made to standardize the quality control methods in accordance with pharmacopoeia standards; however, the methods’ feasibility is still uncertain.
{"title":"[225Ac]Ac-PSMA-617 production method: development of an efficient and reproducible radiolabelling process for establish a clinical routine production","authors":"Michela Aurilio, Aureliana Esposito, Monica Buonanno, Anna Morisco, Costantina Maisto, Stefania Scala, Secondo Lastoria","doi":"10.1186/s41181-025-00344-9","DOIUrl":"10.1186/s41181-025-00344-9","url":null,"abstract":"<div><h3>Background</h3><p>Targeted Alpha Therapy shows very promising clinical results in a cancer treatment and it should be comparable or better than chemotherapy and β-radionuclide therapy, in terms of efficacy and toxicity. The use of α-emission offers advantages over β-emission due to the high linear energy transfer and the limited range in tissue. Actinium-225 is an α-emitter with a half-life of 9.92 days, which is an appropriate half-life for convenient treatment. Actinium-225 is introduced to tumor-targeting vectors through its complexation by a chelating moiety. On this basis, the aim of this study is to develop an [<sup>225</sup>Ac]Ac-PSMA 617 production method, to assess the efficiency and reliability of the radiosynthesis as a support for establish a clinical routine production for metastatic castration resistant prostate cancer treatment.</p><h3>Results</h3><p>different radiolabeling conditions and different reaction times have been used and compared. The best radiochemical yields (> 95%) were obtained when the peptide was dissolved in water and it was used at quantity of 100 µg in gentisic buffer, without stabilizing agent. The reaction was conducted at 97 °C and no significant change in labeling yield was observed when the time reaction increased. This condition ensures an adequate stability at 24 h around 90%.</p><h3>Conclusions</h3><p>the radiolabeling method employed in our experiments has demonstrated consistent reproducibility, enabling us to produce a radiopharmaceutical that meets pharmaceutical-grade standards. Greater difficulties occurred in defining the optimal procedures for quality controls, due to the unique physical properties of actinium. Efforts were made to standardize the quality control methods in accordance with pharmacopoeia standards; however, the methods’ feasibility is still uncertain.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"10 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ejnmmipharmchem.springeropen.com/counter/pdf/10.1186/s41181-025-00344-9","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143904753","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}
Mesothelin is a 40 kDa glycoprotein overexpressed in several cancers, including triple-negative breast cancer (TNBC). The anti-mesothelin single-domain antibody (sdAb, or nanobody) A1 can serve as a radio-theranostic agent, but random DOTA conjugation on lysines yields heterogeneous products.
Results
We reengineered A1-His by directed mutagenesis to produce four single-lysine variants (A1K1-His, A1K2-His, A1K3-His, and A1K4-His). Each was site-specifically conjugated with p-SCN-Bn-DOTA, radiolabeled with 68Ga, and evaluated by PET imaging in mice bearing HCC70 TNBC xenografts, followed by ex vivo biodistribution at 1 h post-injection. All mutants were successfully produced and site-specifically conjugated. A1K1-His showed lower conjugation efficiency and increased liver/spleen retention, whereas A1K3-His exhibited reduced stability. A1K2-His and A1K4-His performed best overall. Removing the His-tag and administering gelofusin further lowered renal uptake. Notably, A1K2 displayed tumor-to-kidney and tumor-to-liver ratios 2.4 and 1.9 times higher, respectively, than A1K4 (p < 0.01).
Conclusions
For the first time, site-specific DOTA conjugation using sdAb derivatives containing a single lysine was achieved, avoiding the production of mixed final compounds. These findings identify 68Ga-DOTA-A1K2 as the leading candidate for mesothelin-expressing tumor imaging with minimal off-target uptake. Ongoing studies will assess its therapeutic utility with 177Lu-DOTA-A1K2. Since these four lysines are conserved in many sdAbs, this strategy may be broadly applicable for site-specific sdAb labeling.
{"title":"Enhancing theranostic potential of anti-mesothelin sdAb through site-specific labeling at a unique conserved lysine by molecular engineering","authors":"Émilien N’Guessan, Florian Raes, Mitra Ahmadi, Sandrine Bacot, Laurent Dumas, Julien Leenhardt, Marlène Debiossat, Clémence André, Jean-Luc Lenormand, Catherine Ghezzi, Daniel Fagret, Charlotte Lombardi, Alexis Broisat","doi":"10.1186/s41181-025-00340-z","DOIUrl":"10.1186/s41181-025-00340-z","url":null,"abstract":"<div><h3>Background</h3><p>Mesothelin is a 40 kDa glycoprotein overexpressed in several cancers, including triple-negative breast cancer (TNBC). The anti-mesothelin single-domain antibody (sdAb, or nanobody) A1 can serve as a radio-theranostic agent, but random DOTA conjugation on lysines yields heterogeneous products.</p><h3>Results</h3><p>We reengineered A1-His by directed mutagenesis to produce four single-lysine variants (A1K1-His, A1K2-His, A1K3-His, and A1K4-His). Each was site-specifically conjugated with p-SCN-Bn-DOTA, radiolabeled with <sup>68</sup>Ga, and evaluated by PET imaging in mice bearing HCC70 TNBC xenografts, followed by ex vivo biodistribution at 1 h post-injection. All mutants were successfully produced and site-specifically conjugated. A1K1-His showed lower conjugation efficiency and increased liver/spleen retention, whereas A1K3-His exhibited reduced stability. A1K2-His and A1K4-His performed best overall. Removing the His-tag and administering gelofusin further lowered renal uptake. Notably, A1K2 displayed tumor-to-kidney and tumor-to-liver ratios 2.4 and 1.9 times higher, respectively, than A1K4 (<i>p</i> < 0.01).</p><h3>Conclusions</h3><p>For the first time, site-specific DOTA conjugation using sdAb derivatives containing a single lysine was achieved, avoiding the production of mixed final compounds. These findings identify <sup>68</sup>Ga-DOTA-A1K2 as the leading candidate for mesothelin-expressing tumor imaging with minimal off-target uptake. Ongoing studies will assess its therapeutic utility with <sup>177</sup>Lu-DOTA-A1K2. Since these four lysines are conserved in many sdAbs, this strategy may be broadly applicable for site-specific sdAb labeling.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"10 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ejnmmipharmchem.springeropen.com/counter/pdf/10.1186/s41181-025-00340-z","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143883669","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}
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