EJNMMI Radiopharmacy and Chemistry最新文献

{"title":"Radiation nanomedicines for cancer treatment: a scientific journey and view of the landscape","authors":"Raymond M. Reilly, Constantine J. Georgiou, Madeline K. Brown, Zhongli Cai","doi":"10.1186/s41181-024-00266-y","DOIUrl":"10.1186/s41181-024-00266-y","url":null,"abstract":"<div><h3>Background</h3><p>Radiation nanomedicines are nanoparticles labeled with radionuclides that emit α- or β-particles or Auger electrons for cancer treatment. We describe here our 15 years scientific journey studying locally-administered radiation nanomedicines for cancer treatment. We further present a view of the radiation nanomedicine landscape by reviewing research reported by other groups.</p><h3>Main body</h3><p>Gold nanoparticles were studied initially for radiosensitization of breast cancer to X-radiation therapy. These nanoparticles were labeled with <sup>111</sup>In to assess their biodistribution after intratumoural vs. intravenous injection. Intravenous injection was limited by high liver and spleen uptake and low tumour uptake, while intratumoural injection provided high tumour uptake but low normal tissue uptake. Further, [<sup>111</sup>In]In-labeled gold nanoparticles modified with trastuzumab and injected iintratumourally exhibited strong tumour growth inhibition in mice with subcutaneous HER2-positive human breast cancer xenografts. In subsequent studies, strong tumour growth inhibition in mice was achieved without normal tissue toxicity in mice with human breast cancer xenografts injected intratumourally with gold nanoparticles labeled with β-particle emitting <sup>177</sup>Lu and modified with panitumumab or trastuzumab to specifically bind EGFR or HER2, respectively. A nanoparticle depot (nanodepot) was designed to incorporate and deliver radiolabeled gold nanoparticles to tumours using brachytherapy needle insertion techniques. Treatment of mice with s.c. 4T1 murine mammary carcinoma tumours with a nanodepot incorporating [<sup>90</sup>Y]Y-labeled gold nanoparticles inserted into one tumour arrested tumour growth and caused an abscopal growth-inhibitory effect on a distant second tumour. Convection-enhanced delivery of [<sup>177</sup>Lu]Lu-AuNPs to orthotopic human glioblastoma multiforme (GBM) tumours in mice arrested tumour growth without normal tissue toxicity. Other groups have explored radiation nanomedicines for cancer treatment in preclinical animal tumour xenograft models using gold nanoparticles, liposomes, block copolymer micelles, dendrimers, carbon nanotubes, cellulose nanocrystals or iron oxide nanoparticles. These nanoparticles were labeled with radionuclides emitting Auger electrons (<sup>111</sup>In, <sup>99m</sup>Tc, <sup>125</sup>I, <sup>103</sup>Pd, <sup>193m</sup>Pt, <sup>195m</sup>Pt), β-particles (<sup>177</sup>Lu, <sup>186</sup>Re, <sup>188</sup>Re, <sup>90</sup>Y, <sup>198</sup>Au, <sup>131</sup>I) or α-particles (<sup>225</sup>Ac, <sup>213</sup>Bi, <sup>212</sup>Pb, <sup>211</sup>At, <sup>223</sup>Ra). These studies employed intravenous or intratumoural injection or convection enhanced delivery. Local administration of these radiation nanomedicines was most effective and minimized normal tissue toxicity.</p><h3>Conclusions</h3><p>Radiation nanomedicines have shown great promise for treating canc","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"9 1","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ejnmmipharmchem.springeropen.com/counter/pdf/10.1186/s41181-024-00266-y","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140826087","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":"GMP production of [18F]FE-PE2I on a TRACERLab FX2 N synthesis module, a radiotracer for in vivo PET imaging of the dopamine transport","authors":"Mélodie Ferrat,&nbsp;Mohammad M. Moein,&nbsp;Carmen Cananau,&nbsp;Tetyana Tegnebratt,&nbsp;Paul Saliba,&nbsp;Fredrik Norman,&nbsp;Carsten Steiger,&nbsp;Klas Bratteby,&nbsp;Erik Samén,&nbsp;Kenneth Dahl,&nbsp;Thuy A. Tran","doi":"10.1186/s41181-024-00269-9","DOIUrl":"10.1186/s41181-024-00269-9","url":null,"abstract":"<div><h3>Background</h3><p>Parkinson's disease is a neurodegenerative disorder that is characterized by a degeneration of the dopaminergic system. Dopamine transporter (DAT) positron emission tomography (PET) imaging has emerged as a powerful and non-invasive method to quantify dopaminergic function in the living brain. The PET radioligand, [¹⁸F]FE-PE2I, a cocaine chemical derivative, has shown promising properties for in vivo PET imaging of DAT, including high affinity and selectivity for DAT, excellent brain permeability, and favorable metabolism. The aim of the current study was to scale up the production of [¹⁸F]FE-PE2I to fulfil the increasing clinical demand for this tracer.</p><h3>Results</h3><p>Thus, a fully automated and GMP-compliant production procedure has been developed using a commercially available radiosynthesis module GE TRACERLab FX2 N. [¹⁸F]FE-PE2I was produced with a radiochemical yield of 39 ± 8% (n = 4, relative [¹⁸F]F⁻ delivered to the module). The synthesis time was 70 min, and the molar activity was 925.3 ± 763 GBq/µmol (250 ± 20 Ci/µmol). The produced [¹⁸F]FE-PE2I was stable over 6 h at room temperature.</p><h3>Conclusion</h3><p>The protocol reliably provides a sterile and pyrogen–free GMP-compliant product.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"9 1","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ejnmmipharmchem.springeropen.com/counter/pdf/10.1186/s41181-024-00269-9","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140820449","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":"99mTc-labeled FAPI compounds for cancer and inflammation: from radiochemistry to the first clinical applications","authors":"Alessandra Boschi,&nbsp;Luca Urso,&nbsp;Licia Uccelli,&nbsp;Petra Martini,&nbsp;Luca Filippi","doi":"10.1186/s41181-024-00264-0","DOIUrl":"10.1186/s41181-024-00264-0","url":null,"abstract":"<div><h3>Background</h3><p>In recent years, fibroblast activating protein (FAP), a biomarker overexpressed by cancer-associated fibroblasts, has emerged as one of the most promising biomarkers in oncology. Similarly, FAP overexpression has been detected in various fibroblast-mediated inflammatory conditions such as liver cirrhosis and idiopathic pulmonary fibrosis. Along this trajectory, FAP-targeted positron emission tomography (PET), utilizing FAP inhibitors (FAPi) labeled with positron emitters, has gained traction as a powerful imaging approach in both cancer and inflammation. However, PET represents a high-cost technology, and its widespread adoption is still limited compared to the availability of gamma cameras. To address this issue, several efforts have been made to explore the potential of [^99mTc]Tc-FAPi tracers as molecular probes for imaging with gamma cameras and single photon emission computed tomography (SPECT).</p><h3>Main body</h3><p>Several approaches have been investigated for labeling FAPi-based compounds with ^99mTc. Specifically, the mono-oxo, tricarbonyl, isonitrile, and HYNIC strategies have been applied to produce [^99mTc]Tc-FAPi tracers, which have been tested in vitro and in animal models. Overall, these labeling approaches have demonstrated high efficiency and strong binding. The resulting [^99mTc]Tc-FAPi tracers have shown high specificity for FAP-positive cells and xenografts in both in vitro and animal model studies, respectively. However, the majority of [^99mTc]Tc-FAPi tracers have exhibited variable levels of lipophilicity, leading to preferential excretion through the hepatobiliary route and undesirable binding to lipoproteins. Consequently, efforts have been made to synthesize more hydrophilic FAPi-based compounds to improve pharmacokinetic properties and achieve a more favorable biodistribution, particularly in the abdominal region. SPECT imaging with [^99mTc]Tc-FAPi has yielded promising results in patients with gastrointestinal tumors, demonstrating comparable or superior diagnostic performance compared to other imaging modalities. Similarly, encouraging outcomes have been observed in subjects with gliomas, lung cancer, breast cancer, and cervical cancer. Beyond oncological applications, [^99mTc]Tc-FAPi-based imaging has been successfully employed in myocardial and idiopathic pulmonary fibrosis.</p><h3>Conclusions</h3><p>This overview focuses on the various radiochemical strategies for obtaining [^99mTc]Tc-FAPi tracers, highlighting the main challenges encountered and possible solutions when applying each distinct approach. Additionally, it covers the preclinical and initial clinical applications of [^99mTc]Tc-FAPi in cancer and inflammation.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"9 1","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ejnmmipharmchem.springeropen.com/counter/pdf/10.1186/s41181-024-00264-0","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140820450","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":"Advancing 6-bromo-7-[11C]methylpurine to clinical use: improved regioselective radiosynthesis, non-clinical toxicity data and human dosimetry estimates","authors":"Severin Mairinger,&nbsp;Matthias Jackwerth,&nbsp;Ondřej Soukup,&nbsp;Matthias Blaickner,&nbsp;Clemens Decristoforo,&nbsp;Lukas Nics,&nbsp;Jens Pahnke,&nbsp;Marcus Hacker,&nbsp;Markus Zeitlinger,&nbsp;Oliver Langer","doi":"10.1186/s41181-024-00265-z","DOIUrl":"10.1186/s41181-024-00265-z","url":null,"abstract":"<div><h3>Background</h3><p>6-Bromo-7-[¹¹C]methylpurine ([¹¹C]BMP) is a radiotracer for positron emission tomography (PET) to measure multidrug resistance-associated protein 1 (MRP1) transport activity in different tissues. Previously reported radiosyntheses of [¹¹C]BMP afforded a mixture of 7- and 9-[¹¹C]methyl regioisomers. To prepare for clinical use, we here report an improved regioselective radiosynthesis of [¹¹C]BMP, the results of a non-clinical toxicity study as well as human dosimetry estimates based on mouse PET data.</p><h3>Results</h3><p>[¹¹C]BMP was synthesised by regioselective <i>N</i>^<i>7</i>-methylation of 6-bromo-7H-purine (prepared under good manufacturing practice) with [¹¹C]methyl triflate in presence of 2,2,6,6-tetramethylpiperidine magnesium chloride in a TRACERlab™ FX2 C synthesis module. [¹¹C]BMP was obtained within a total synthesis time of approximately 43 min in a decay-corrected radiochemical yield of 20.5 ± 5.2%, based on starting [¹¹C]methyl iodide, with a radiochemical purity &gt; 99% and a molar activity at end of synthesis of 197 ± 130 GBq/μmol (<i>n</i> = 28). An extended single-dose toxicity study conducted in male and female Wistar rats under good laboratory practice after single intravenous (i.v.) administration of unlabelled BMP (2 mg/kg body weight) revealed no test item related adverse effects. Human dosimetry estimates, based on dynamic whole-body PET data in female C57BL/6J mice, suggested that an i.v. injected activity amount of 400 MBq of [¹¹C]BMP will deliver an effective dose in the typical range of ¹¹C-labelled radiotracers.</p><h3>Conclusions</h3><p>[¹¹C]BMP can be produced in sufficient amounts and acceptable quality for clinical use. Data from the non-clinical safety evaluation showed no adverse effects and suggested that the administration of [¹¹C]BMP will be safe and well tolerated in humans.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"9 1","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ejnmmipharmchem.springeropen.com/counter/pdf/10.1186/s41181-024-00265-z","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140814115","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":"Small animal PET imaging with the 68Ga-labeled pH (low) insertion peptide-like peptide YJL-4 in a triple-negative breast cancer mouse model","authors":"YueHua Chen,&nbsp;ShuangShuang Song,&nbsp;YanQin Sun,&nbsp;FengYu Wu,&nbsp;GuangJie Yang,&nbsp;ZhenGuang Wang,&nbsp;MingMing Yu","doi":"10.1186/s41181-024-00267-x","DOIUrl":"10.1186/s41181-024-00267-x","url":null,"abstract":"<div><h3>Background</h3><p>The aim of this study was to prepare a novel ⁶⁸Ga-labeled pH (low) insertion peptide (pHLIP)-like peptide, YJL-4, and determine its value for the early diagnosis of triple-negative breast cancer (TNBC) via in vivo imaging of tumor-bearing nude mice. The novel peptide YJL-4 was designed using a template-assisted method and synthesized by solid-phase peptide synthesis. After modification with the chelator 1,4,7‑triazacyclononane-N,N′,N″-triacetic acid (NOTA), the peptide was labeled with ⁶⁸Ga. Then, the biodistribution of ⁶⁸Ga-YJL-4 in tumor-bearing nude mice was investigated, and the mice were imaged by small animal positron emission tomography (PET).</p><h3>Results</h3><p>The radiochemical yield and radiochemical purity of ⁶⁸Ga-YJL-4 were 89.5 ± 0.16% and 97.95 ± 0.06%, respectively. The biodistribution of ⁶⁸Ga-YJL-4 in tumors (5.94 ± 1.27% ID/g, 6.72 ± 1.69% ID/g and 4.54 ± 0.58% ID/g at 1, 2 and 4 h after injection, respectively) was significantly greater than that of the control peptide in tumors at the corresponding time points (<i>P</i> &lt; 0.01). Of the measured off-target organs, ⁶⁸Ga-YJL-4 was highly distributed in the liver and blood. The small animal PET imaging results were consistent with the biodistribution results. The tumors were visualized by PET at 2 and 4 h after the injection of ⁶⁸Ga-YJL-4. No tumors were observed in the control group.</p><h3>Conclusions</h3><p>The novel pHLIP family peptide YJL-4 can adopt an <i>α-</i>helical structure for easy insertion into the cell membrane in an acidic environment. ⁶⁸Ga-YJL-4 was produced in high radiochemical yield with good stability and can target TNBC tissue. Moreover, the strong concentration of radioactive ⁶⁸Ga-YJL-4 in the abdomen does not hinder the imaging of early TNBC.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"9 1","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ejnmmipharmchem.springeropen.com/counter/pdf/10.1186/s41181-024-00267-x","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140807309","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":"Radiolabeled 15-mer peptide internalization is mediated by megalin (LRP2 receptor) in a CRISPR/Cas9-based LRP2 knockout human kidney cell model","authors":"Anna Durinova,&nbsp;Lucie Smutna,&nbsp;Pavel Barta,&nbsp;Rajamanikkam Kamaraj,&nbsp;Tomas Smutny,&nbsp;Bernhard Schmierer,&nbsp;Petr Pavek,&nbsp;Frantisek Trejtnar","doi":"10.1186/s41181-024-00262-2","DOIUrl":"10.1186/s41181-024-00262-2","url":null,"abstract":"<div><h3>Background</h3><p>Megalin (LRP2 receptor) mediates the endocytosis of radiolabeled peptides into proximal tubular kidney cells, which may cause nephrotoxicity due to the accumulation of a radioactive tracer. The study aimed to develop a cellular model of human kidney HK2 cells with <i>LRP2</i> knockout (KO) using CRISPR/Cas9 technique. This model was employed for the determination of the megalin-mediated accumulation of ⁶⁸Ga- and ^99mTc-labeled 15-mer peptide developed to target the vascular endothelial growth factor (VEGF) receptor in oncology radiodiagnostics.</p><h3>Results</h3><p>The gene editing in the <i>LRP2</i> KO model was verified by testing two well-known megalin ligands when higher viability of KO cells was observed after gentamicin treatment at cytotoxic concentrations and lower FITC-albumin internalization by the KO cells was detected in accumulation studies. Fluorescent-activated cell sorting was used to separate genetically modified <i>LRP2</i> KO cell subpopulations. Moreover, flow cytometry with a specific antibody against megalin confirmed <i>LRP2</i> knockout. The verified KO model identified both ⁶⁸Ga- and ^99mTc-radiolabeled 15-mer peptides as megalin ligands in accumulation studies. We found that both radiolabeled 15-mers enter <i>LRP2</i> KO HK2 cells to a lesser extent compared to parent cells. Differences in megalin-mediated cellular uptake depending on the radiolabeling were not observed. Using biomolecular docking, the interaction site of the 15-mer with megalin was also described.</p><h3>Conclusion</h3><p>The CRISPR/Cas9 knockout of <i>LRP2</i> in human kidney HK2 cells is an effective approach for the determination of radiopeptide internalization mediated by megalin. This in vitro method provided direct molecular evidence for the cellular uptake of radiolabeled anti-VEGFR 15-mer peptides via megalin.</p><h3>Graphical abstract</h3>\u0000<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":4.6,"publicationDate":"2024-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ejnmmipharmchem.springeropen.com/counter/pdf/10.1186/s41181-024-00262-2","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140619696","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":"Automated radiolabelling of [68Ga]Ga-PSMA-11 (gallium (68Ga)-gozetotide) using the Locametz® kit and two generators","authors":"Elke A. van Brandwijk,&nbsp;Else A. Aalbersberg,&nbsp;Arman S. Hosseini,&nbsp;Alwin D. R. Huitema,&nbsp;Jeroen J. M. A. Hendrikx","doi":"10.1186/s41181-024-00260-4","DOIUrl":"10.1186/s41181-024-00260-4","url":null,"abstract":"<div><h3>Background</h3><p>Steps have been taken by pharmaceutical companies to obtain marketing authorisation of PSMA ligands in the European Union. Since December 2022, Locametz® (PSMA-11, gozetotide) is licensed as kit for manual radiolabelling with gallium-68 and commercially available since mid-2023. The Summary of Product Characteristic (SmPC) describes manual radiolabelling with a maximum activity after radiolabelling of 1369 MBq. We aimed for radiolabelling with a higher activity to increase production efficiency, and thus, automated radiolabelling is strongly preferred over manual radiolabelling to reduce radiation exposure to personnel. The aim of this study was to develop and validate a method for automated radiolabelling of the Locametz® kit using ~ 2000 MBq of gallium-68 eluate for radiolabelling.</p><h3>Results</h3><p>Automated radiolabelling of [⁶⁸Ga]Ga-PSMA-11 using the Locametz® kit provided a product which complies to the Ph. Eur., had a shelf-life of 6 h at room temperature, and theoretically reduced radiation exposure 5.7 times. Radiolabelling with one and two generator(s) resulted in a radiochemical yield of 91–102% and 96–101% after preparation, respectively. The radiochemical purity ranged from 98.0 to 99.6% for radiolabelling with one generator and ranged from 98.4 to 99.3% for radiolabelling with two generators with similar stability. The activity of the final product was much higher when using two generators, 1961–2035 MBq compared to 740–1260 MBq, which leads to ~ 1.5 times more patient syringes available per preparation.</p><h3>Conclusion</h3><p>Automated radiolabelling of [⁶⁸Ga]Ga-PSMA-11 using the Locametz® kit with higher gallium-68 activity than specified in the SmPC results in a product that is in compliance with the Ph. Eur. monograph and has a shelf-life of 6 h at room temperature. Radiolabelling with two generators proved possible and resulted in a product with similar quality but with much higher efficiency.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"9 1","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ejnmmipharmchem.springeropen.com/counter/pdf/10.1186/s41181-024-00260-4","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140606216","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":"Comparison of approaches for increasing affinity of affibody molecules for imaging of B7-H3: dimerization and affinity maturation","authors":"Maryam Oroujeni,&nbsp;Matilda Carlqvist,&nbsp;Eva Ryer,&nbsp;Anna Orlova,&nbsp;Vladimir Tolmachev,&nbsp;Fredrik Y. Frejd","doi":"10.1186/s41181-024-00261-3","DOIUrl":"10.1186/s41181-024-00261-3","url":null,"abstract":"<div><h3>Background</h3><p>Radionuclide molecular imaging can be used to visualize the expression levels of molecular targets. Affibody molecules, small and high affinity non-immunoglobulin scaffold-based proteins, have demonstrated promising properties as targeting vectors for radionuclide tumour imaging of different molecular targets. B7-H3 (CD276), an immune checkpoint protein belonging to the B7 family, is overexpressed in different types of human malignancies. Visualization of overexpression of B7-H3 in malignancies enables stratification of patients for personalized therapies. Affinity maturation of anti-B7-H3 Affibody molecules as an approach to improve the binding affinity and targeting properties was recently investigated. In this study, we tested the hypothesis that a dimeric format may be an alternative option to increase the apparent affinity of Affibody molecules to B7-H3 and accordingly improve imaging contrast.</p><h3>Results</h3><p>Two dimeric variants of anti-B7-H3 Affibody molecules were produced (designated Z_AC12*-Z_AC12*-GGGC and Z_AC12*-Z_{Taq_3}-GGGC). Both variants were labelled with Tc-99m (^99mTc) and demonstrated specific binding to B7-H3-expressing cells in vitro. [^99mTc]Tc-Z_AC12*-Z_AC12*-GGGC showed subnanomolar affinity (K_D1=0.28 ± 0.10 nM, weight = 68%), which was 7.6-fold higher than for [^99mTc]Tc-Z_AC12*-Z_{Taq_3}-GGGC (K_D=2.1 ± 0.9 nM). Head-to-head biodistribution of both dimeric variants of Affibody molecules compared with monomeric affinity matured SYNT-179 (all labelled with ^99mTc) in mice bearing B7-H3-expressing SKOV-3 xenografts demonstrates that both dimers have lower tumour uptake and lower tumour-to-organ ratios compared to the SYNT-179 Affibody molecule.</p><h3>Conclusion</h3><p>The improved functional affinity by dimerization does not compensate the disadvantage of increased molecular size for imaging purposes.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"9 1","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ejnmmipharmchem.springeropen.com/counter/pdf/10.1186/s41181-024-00261-3","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140559482","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":"Production of [211At]NaAt solution under GMP compliance for investigator-initiated clinical trial","authors":"Sadahiro Naka,&nbsp;Kazuhiro Ooe,&nbsp;Yoshifumi Shirakami,&nbsp;Kenta Kurimoto,&nbsp;Toshihiro Sakai,&nbsp;Kazuhiro Takahashi,&nbsp;Atsushi Toyoshima,&nbsp;Yang Wang,&nbsp;Hiromitsu Haba,&nbsp;Hiroki Kato,&nbsp;Noriyuki Tomiyama,&nbsp;Tadashi Watabe","doi":"10.1186/s41181-024-00257-z","DOIUrl":"10.1186/s41181-024-00257-z","url":null,"abstract":"<div><h3>Background</h3><p>The alpha emitter astatine-211 (²¹¹At) is garnering attention as a novel targeted alpha therapy for patients with refractory thyroid cancer resistant to conventional therapy using beta emitter radioiodine (¹³¹I). Herein, we aimed to establish a robust method for the manufacturing and quality control of [²¹¹At]NaAt solution for intravenous administration under the good manufacturing practice guidelines for investigational products to conduct an investigator-initiated clinical trial.</p><h3>Results</h3><p>²¹¹At was separated and purified via dry distillation using irradiated Bi plates containing ²¹¹At obtained by the nuclear reaction of ²⁰⁹Bi(⁴He, 2n)²¹¹At. After purification, the ²¹¹At trapped in the cold trap was collected in a reaction vessel using 15 mL recovery solution (1% ascorbic acid and 2.3% sodium hydrogen carbonate). After stirring the ²¹¹At solution for 1 h inside a closed system, the reaction solution was passed through a sterile 0.22 μm filter placed in a Grade A controlled area and collected in a product vial to prepare the [²¹¹At]NaAt solution. According to the 3-lot tests, decay collected radioactivity and radiochemical yield of [²¹¹At]NaAt were 78.8 ± 6.0 MBq and 40 ± 3%, respectively. The radiochemical purity of [²¹¹At]At⁻ obtained via ion-pair chromatography at the end of synthesis (EOS) was 97 ± 1%, and remained &gt; 96% 6 h after EOS; it was detected at a retention time (RT) 3.2–3.3 min + RT of I⁻. LC-MS analysis indicated that this principal peak corresponded with an astatide ion (m/z = 210.988046). In gamma-ray spectrometry, the ²¹¹At-related peaks were identified (X-ray: 76.9, 79.3, 89.3, 89.8, and 92.3 keV; γ-ray: 569.7 and 687.0 keV), whereas the peak at 245.31 keV derived from ²¹⁰At was not detected during the 22 h continuous measurement. The target material, Bi, was below the 9 ng/mL detection limit in all lots of the finished product. The pH of the [²¹¹At]NaAt solution was 7.9–8.6; the concentration of ascorbic acid was 9–10 mg/mL. Other quality control tests, including endotoxin and sterility tests, confirmed that the [²¹¹At]NaAt solution met all quality standards.</p><h3>Conclusions</h3><p>We successfully established a stable method of [²¹¹At]NaAt solution that can be administered to humans intravenously as an investigational product.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"9 1","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ejnmmipharmchem.springeropen.com/counter/pdf/10.1186/s41181-024-00257-z","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140556096","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":"Improved automated one-pot two-step radiosynthesis of (S)-[18F]FETrp, a radiotracer for PET imaging of indoleamine 2,3-dioxygenase 1 (IDO1)","authors":"Aurélie Maisonial-Besset,&nbsp;David Kryza,&nbsp;Klaus Kopka,&nbsp;Sophie Levesque,&nbsp;Emmanuel Moreau,&nbsp;Barbara Wenzel,&nbsp;Jean-Michel Chezal","doi":"10.1186/s41181-024-00256-0","DOIUrl":"10.1186/s41181-024-00256-0","url":null,"abstract":"<div><h3>Background</h3><p>(<i>S</i>)-[¹⁸F]FETrp is a promising PET radiotracer for imaging IDO1 activity, one of the main enzymes involved in the tryptophan metabolism that plays a key role in several diseases including cancers. To date, the radiosynthesis of this tryptophan analogue remains highly challenging due to partial racemization occurring during the nucleophilic radiofluorination step. This work aims to develop a short, epimerization-free and efficient automated procedure of (<i>S</i>)-[¹⁸F]FETrp from a corresponding enantiopure tosylate precursor.</p><h3>Results</h3><p>Enantiomerically pure (<i>S</i>)<i>-</i> and (<i>R</i>)-FETrp references as well as tosylate precursors (<i>S</i>)- and (<i>R</i>)-3 were obtained from corresponding <i>N</i>^<i>a</i>-Boc-(L and D)-tryptophan in 2 and 4 steps, respectively. Manual optimisation of the radiolabelling conditions resulted in &gt; 90% radiochemical conversion with more than 99% enantiomeric purity. Based on these results, the (<i>S</i>)-[¹⁸F]FETrp radiosynthesis was fully automated on a SynChrom R&amp;D EVOI module to produce the radiotracer in 55.2 ± 7.5% radiochemical yield, 99.9% radiochemical purity, 99.1 ± 0.5% enantiomeric excess, and molar activity of 53.2 ± 9.3 GBq/µmol (<i>n</i> = 3).</p><h3>Conclusions</h3><p>To avoid racemisation and complicated purification processes, currently encountered for the radiosynthesis of (<i>S</i>)-[¹⁸F]FETrp, we report herein significant improvements, including a versatile synthesis of enantiomerically pure tosylate precursor and reference compound and a convenient one-pot two-step automated procedure for the radiosynthesis of (<i>S</i>)-[¹⁸F]FETrp. This optimised and robust production method could facilitate further investigations of this relevant PET radiotracer for imaging IDO1 activity.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"9 1","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ejnmmipharmchem.springeropen.com/counter/pdf/10.1186/s41181-024-00256-0","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140334165","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}