EJNMMI Radiopharmacy and Chemistry最新文献

{"title":"In vivo evaluation of tumor uptake and bio-distribution of 99mTc-labeled 1-thio-β-D-glucose and 5-thio-D-glucose in mice model","authors":"Fabian Muehlberg,&nbsp;Konrad Mohnike,&nbsp;Oliver S. Grosser,&nbsp;Maciej Pech,&nbsp;Juergen Goldschmidt,&nbsp;Karl-Heinz Smalla,&nbsp;Ricarda Seidensticker,&nbsp;Muzaffer Reha Ümütlü,&nbsp;Sinan Deniz,&nbsp;Jens Ricke,&nbsp;Ingo G. Steffen,&nbsp;Osman Öcal,&nbsp;Max Seidensticker","doi":"10.1186/s41181-024-00253-3","DOIUrl":"10.1186/s41181-024-00253-3","url":null,"abstract":"<div><h3>Background</h3><p>To investigate the capacity of ^99mTc-labeled 1-thio-β-D-glucose (1-TG) and 5-thio-D-glucose (5-TG) to act as a marker for glucose consumption in tumor cells in vivo as well as to evaluate the biodistribution of 1-TG and 5-TG. We investigated the biodistribution, including tumor uptake, of 1-TG and 5-TG at various time points after injection (0.5, 2 and 4 h) in human colorectal carcinoma (HCT-116) and human lung adenocarcinoma (A549) xenograft bearing nude mice (N = 4 per tracer and time point).</p><h3>Results</h3><p>Ex vivo biodistribution studies revealed a moderate uptake with a maximum tumor-to-muscle ratio of 4.22 ± 2.7 and 2.2 ± 1.3 (HCT-116) and of 3.2 ± 1.1 and 4.1 ± 1.3 (A549) for 1-TG and 5-TG, respectively, with a peak at 4 h for 1-TG and 5-TG. Biodistribution revealed a significantly higher uptake compared to blood in kidneys (12.18 ± 8.77 and 12.69 ± 8.93%ID/g at 30 min) and liver (2.6 ± 2.8%ID/g) for 1-TG and in the lung (7.24 ± 4.1%ID/g), liver (6.38 ± 2.94%ID/g), and kidneys (4.71 ± 1.97 and 4.81 ± 1.91%ID/g) for 5-TG.</p><h3>Conclusions</h3><p>1-TG and 5-TG showed an insufficient tumor uptake with a moderate tumor-to-muscle ratio, not reaching the levels of commonly used tracer, for diagnostic use in human colorectal carcinoma and human lung adenocarcinoma xenograft model.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"9 1","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ejnmmipharmchem.springeropen.com/counter/pdf/10.1186/s41181-024-00253-3","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140326215","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":"Expanding a peptide-covalent probe hybrid for PET imaging of S. aureus driven focal infections","authors":"Jyotsna Bhatt Mitra,&nbsp;Saurav Chatterjee,&nbsp;Anuj Kumar,&nbsp;Elina Khatoon,&nbsp;Ashok Chandak,&nbsp;Sutapa Rakshit,&nbsp;Anupam Bandyopadhyay,&nbsp;Archana Mukherjee","doi":"10.1186/s41181-024-00252-4","DOIUrl":"10.1186/s41181-024-00252-4","url":null,"abstract":"<div><h3>Background</h3><p>The urgent demand for innovative theranostic strategies to combat bacterial resistance to antibiotics is evident, with substantial implications for global health. Rapid diagnosis of life-threatening infections can expedite treatment, improving patient outcomes. Leveraging diagnostic modalities i.e., positron emission tomography (PET) and single photon emission computed tomography (SPECT) for detecting focal infections has yielded promising results. Augmenting the sensitivity of current PET and SPECT tracers could enable effective imaging of pathogenic bacteria, including drug-resistant strains.UBI (29–41), an antimicrobial peptide (AMP) fragment recognizes the <i>S. aureus</i> membrane through electrostatic binding. Radiolabeled UBI (29–41) is a promising SPECT and PET-based tracer for detecting focal infections. 2-APBA (2-acetyl-phenyl-boronic acid), a non-natural amino acid, specifically targets lysyl-phosphatidyl-glycerol (lysyl-PG) on the <i>S. aureus</i> membranes, particularly in AMP-resistant strains. We propose that combining UBI with 2-APBA could enhance the diagnostic potential of radiolabeled UBI.</p><h3>Results</h3><p>Present work aimed to compare the diagnostic potential of two radiolabeled peptides, namely UBI (29–41) and 2-APBA modified UBI (29–41), referred to as UBI and UBI-APBA. APBA modification imparted antibacterial activity to the initially non-bactericidal UBI against <i>S. aureus</i> by inducing a loss of membrane potential. The antibacterial activity demonstrated by UBI-APBA can be ascribed to the synergistic interaction of both UBI and UBI-APBA on the bacterial membrane. To enable PET imaging, we attached the chelator 1,4,7-triazacyclononane 1-glutaric acid 4,7-acetic acid (NODAGA) to the peptides for complexation with the positron emitter Gallium-68 (⁶⁸Ga). Both NODAGA conjugates were radiolabeled with ⁶⁸Ga with high radiochemical purity. The resultant ⁶⁸Ga complexes were stable in phosphate-buffered saline and human serum. Uptake of these complexes was observed in <i>S. aureus</i> but not in mice splenocytes, indicating the selective nature of their interaction. Additionally, the APBA conjugate exhibited superior uptake in <i>S. aureus</i> while preserving the selectivity of the parent peptide. Furthermore, [⁶⁸Ga]Ga-UBI-APBA demonstrated accumulation at the site of infection in rats, with an improved target-to-non-target ratio, as evidenced by ex-vivo biodistribution and PET imaging.</p><h3>Conclusions</h3><p>Our findings suggest that linking UBI, as well as AMPs in general, with APBA shows promise as a strategy to augment the theranostic potential of these molecules.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"9 1","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ejnmmipharmchem.springeropen.com/counter/pdf/10.1186/s41181-024-00252-4","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140292300","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-target production of [11C]CH4 from a nitrogen/hydrogen gas target as a function of beam current, irradiation time, and target temperature","authors":"Semi Helin,&nbsp;Johan Rajander,&nbsp;Jussi Aromaa,&nbsp;Eveliina Arponen,&nbsp;Jatta S. Helin,&nbsp;Olof Solin","doi":"10.1186/s41181-024-00255-1","DOIUrl":"10.1186/s41181-024-00255-1","url":null,"abstract":"<div><h3>Background</h3><p>Production of [¹¹C]CH₄ from gas targets is notorious for weak performance with respect to yield, especially when using high beam currents. Post-target conversion of [¹¹C]CO₂ to [¹¹C]CH₄ is a widely used roundabout method in ¹¹C-radiochemistry, but the added complexity increase the challenge to control carrier carbon. Thus in-target-produced [¹¹C]CH₄ is superior with respect to molar activity. We studied the in-target production of [¹¹C]CO₂ and [¹¹C]CH₄ from nitrogen gas targets as a function of beam current, irradiation time, and target temperature.</p><h3>Results</h3><p>[¹¹C]CO₂ production was practically unchanged across the range of varied parameters, but the [¹¹C]CH₄ yield, presented in terms of saturation yield Y_SAT(¹¹CH₄), had a negative correlation with beam current and a positive correlation with target chamber temperature. A formulated model equation indicates behavior where the [¹¹C]CH₄ formation follows a parabolic graph as a function of beam current. The negative square term, i.e., the yield loss, is postulated to arise from Haber–Bosch-like NH₃ formation: N₂ + 3H₂ → 2NH₃. The studied conditions suggest that the NH₃ (liq.) would be condensed on the target chamber walls, thus depleting the hydrogen reserve needed for the conversion of nascent ¹¹C to [¹¹C]CH₄.</p><h3>Conclusions</h3><p>[¹¹C]CH₄ production can be improved by increasing the target chamber temperature, which is presented in a mathematical formula. Our observations have implications for targetry design (geometry, gas volume and composition, pressure) and irradiation conditions, providing specific knowledge to enhance [¹¹C]CH₄ production at high beam currents. Increased [¹¹C]CH₄ radioactivity is an obvious benefit in radiosynthesis in terms of product yield and molar radioactivity.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"9 1","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ejnmmipharmchem.springeropen.com/counter/pdf/10.1186/s41181-024-00255-1","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140209575","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":"Validation of a size exclusion method for concomitant purification and formulation of peptide radiopharmaceuticals","authors":"Sebastian Martin,&nbsp;Lennard Wendlinger,&nbsp;Alexandra Litvinenko,&nbsp;Radmila Faizova,&nbsp;Margret Schottelius","doi":"10.1186/s41181-024-00254-2","DOIUrl":"10.1186/s41181-024-00254-2","url":null,"abstract":"<div><h3>Background</h3><p>Both in clinical routine and in preclinical research, the established standard procedure for the final purification of radiometal-labeled peptide radiopharmaceuticals is cartridge-based reversed-phase (RP) solid phase extraction (SPE). It allows the rapid and quantitative separation of the radiolabeled peptide from hydrophilic impurities and easy integration into automated synthesis procedures. However, product elution from RP cartridges necessitates the use of organic solvents and product recovery is sometimes limited. Thus, an alternative purification method based on commercially available size exclusion cartridges was investigated.</p><h3>Results</h3><p>Since most peptide radiopharmaceuticals have a molecular weight &gt; 1 kDa, Sephadex G10 cartridges with a molecular size cut-off of 700 Da were used for the final purification of a broad palette of ⁶⁸Ga-, ⁶⁴Cu- and ^99mTc-labeled experimental peptide radiotracers as well as the clinically relevant ligand PSMA-617. Results (radiochemical purity (RCP, determined by ITLC), recovery from the solid support) were compared to the respective standard RP-SPE method. Generally, retention of unreacted ⁶⁸Ga, ⁶⁴Cu and ^99mTc salts on the G10 cartridges was quantitative up to the specified elution volume (1.2 mL) for ⁶⁸Ga and ^99mTc and 99.6% for ⁶⁴Cu. Even at increased elution volumes of 1.5-2 mL, RCPs of the eluted ⁶⁸Ga- and ^99mTc -radiopeptides were &gt; 99%. For all peptides with a molecular weight ≥ 2 kDa, product recovery from the G10 cartridges was consistently &gt; 85% upon respective adjustment of the elution volume. Product recovery was lowest for [⁶⁸Ga]Ga-PSMA-617 (67%, 1.2 mL to 84%, 2 mL). The pH of the final product solution was found to be volume-dependent (1.2 mL: pH 6.3; 1.5 mL: pH 5.9; 2 mL: pH 5.5). Notably, the G10 cartridges were reused up to 20 times without compromising performance, and implementation of the method in an automated radiosynthesis procedure was successful.</p><h3>Conclusions</h3><p>Overall, size exclusion purification yielded all peptide radiopharmaceuticals in excellent radiochemical purities (&gt; 99%) in saline within 10–12 min. Although product recovery is marginally inferior to classical SPE purifications, this method has the advantage of completely avoiding organic solvents and representing a cost-effective, easy-to-implement purification approach for automated radiotracer synthesis.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"9 1","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ejnmmipharmchem.springeropen.com/counter/pdf/10.1186/s41181-024-00254-2","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140183374","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":"Correction: Physiologically based radiopharmacokinetic (PBRPK) modeling to simulate and analyze radiopharmaceutical therapies: studies of non-linearities, multi-bolus injections, and albumin binding","authors":"Ali Fele‑Paranj,&nbsp;Babak Saboury,&nbsp;Carlos Uribe,&nbsp;Arman Rahmim","doi":"10.1186/s41181-024-00251-5","DOIUrl":"10.1186/s41181-024-00251-5","url":null,"abstract":"","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"9 1","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ejnmmipharmchem.springeropen.com/counter/pdf/10.1186/s41181-024-00251-5","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140164220","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis and evaluation of fluorine-18 labelled tetrazines as pre-targeting imaging agents for PET","authors":"Eva Schlein,&nbsp;Johanna Rokka,&nbsp;Luke R. Odell,&nbsp;Sara Lopes van den Broek,&nbsp;Matthias M. Herth,&nbsp;Umberto M. Battisti,&nbsp;Stina Syvänen,&nbsp;Dag Sehlin,&nbsp;Jonas Eriksson","doi":"10.1186/s41181-024-00250-6","DOIUrl":"10.1186/s41181-024-00250-6","url":null,"abstract":"<div><h3>Background</h3><p>The brain is a challenging target for antibody-based positron emission tomography (immunoPET) imaging due to the restricted access of antibody-based ligands through the blood–brain barrier (BBB). To overcome this physiological obstacle, we have previously developed bispecific antibody ligands that pass through the BBB via receptor-mediated transcytosis. While these radiolabelled ligands have high affinity and specificity, their long residence time in the blood and brain, typical for large molecules, poses another challenge for PET imaging. A viable solution could be a two-step pre-targeting approach which involves the administration of a tagged antibody that accumulates at the target site in the brain and then clears from the blood, followed by administration of a small radiolabelled molecule with fast kinetics. This radiolabelled molecule can couple to the tagged antibody and thereby make the antibody localisation visible by PET imaging. The in vivo linkage can be achieved by using the inverse electron demand Diels–Alder reaction (IEDDA), with trans-cyclooctene (TCO) and tetrazine groups participating as reactants. In this study, two novel ¹⁸F-labelled tetrazines were synthesized and evaluated for their potential use as pre-targeting imaging agents, i.e., for their ability to rapidly enter the brain and, if unbound, to be efficiently cleared with minimal background retention.</p><h3>Results</h3><p>The two compounds, a methyl tetrazine [¹⁸F]MeTz and an H-tetrazine [¹⁸F]HTz were radiolabelled using a two-step procedure via [¹⁸F]F-Py-TFP synthesized on solid support followed by amidation with amine-bearing tetrazines, resulting in radiochemical yields of 24% and 22%, respectively, and a radiochemical purity of &gt; 96%. In vivo PET imaging was performed to assess their suitability for in vivo pre-targeting. Time-activity curves from PET-scans showed [¹⁸F]MeTz to be the more pharmacokinetically suitable agent, given its fast and homogenous distribution in the brain and rapid clearance. However, in terms of rection kinetics, H-tetrazines are advantageous, exhibiting faster reaction rates in IEDDA reactions with dienophiles like trans-cyclooctenes, making [¹⁸F]HTz potentially more beneficial for pre-targeting applications.</p><h3>Conclusion</h3><p>This study demonstrates a significant potential of [¹⁸F]MeTz and [¹⁸F]HTz as agents for pre-targeted PET brain imaging due to their efficient brain uptake, swift clearance and appropriate chemical stability.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"9 1","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ejnmmipharmchem.springeropen.com/counter/pdf/10.1186/s41181-024-00250-6","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140038476","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 characterisation of gallium-68 labeled ferrichrome siderophore stereoisomers for PET imaging applications","authors":"Kristyna Krasulova,&nbsp;Barbora Neuzilova,&nbsp;Katerina Dvorakova Bendova,&nbsp;Zbynek Novy,&nbsp;Miroslav Popper,&nbsp;Marian Hajduch,&nbsp;Milos Petrik","doi":"10.1186/s41181-024-00249-z","DOIUrl":"10.1186/s41181-024-00249-z","url":null,"abstract":"<div><h3>Background</h3><p>Siderophores are small iron-binding molecules produced by microorganisms to facilitate iron acquisition from the environment. Radiolabelled siderophores offer a promising solution for infection imaging, as they can specifically target the pathophysiological mechanisms of pathogens. Gallium-68 can replace the iron in siderophores, enabling molecular imaging with positron emission tomography (PET). Stereospecific interactions play a crucial role in the recognition of receptors, transporters, and iron utilisation. Furthermore, these interactions have an impact on the host environment, affecting pharmacokinetics and biodistribution. This study examines the influence of siderophore stereoisomerism on imaging properties, with a focus on ferrirubin (FR) and ferrirhodin (FRH), two <i>cis–trans</i> isomeric siderophores of the ferrichrome type.</p><h3>Results</h3><p>Tested siderophores were labelled with gallium-68 with high radiochemical purity. The resulting complexes differed in their in vitro characteristics. [⁶⁸Ga]Ga-FRH showed less hydrophilic properties and higher protein binding values than [⁶⁸Ga]Ga-FR. The stability studies confirmed the high radiochemical stability of both [⁶⁸Ga]Ga-siderophores in all examined media. Both siderophores were found to be taken up by <i>S. aureus, K. pneumoniae</i> and <i>P. aeruginosa</i> with similar efficacy. The biodistribution tested in normal mice showed rapid renal clearance with low blood pool retention and fast clearance from examined organs for [⁶⁸Ga]Ga-FR, whereas [⁶⁸Ga]Ga-FRH showed moderate retention in blood, resulting in slower pharmacokinetics. PET/CT imaging of mice injected with [⁶⁸Ga]Ga-FR and [⁶⁸Ga]Ga-FRH confirmed findings from ex vivo biodistribution studies. In a mouse model of <i>S. aureus</i> myositis, both radiolabeled siderophores showed radiotracer accumulation at the site of infection.</p><h3>Conclusions</h3><p>The ⁶⁸Ga-complexes of stereoisomers ferrirubin and ferrirhodin revealed different pharmacokinetic profiles. In vitro uptake was not affected by isomerism. Both compounds had uptake with the same bacterial culture with similar efficacy. PET/CT imaging showed that the [⁶⁸Ga]Ga-complexes accumulate at the site of <i>S. aureus</i> infection, highlighting the potential of [⁶⁸Ga]Ga-FR as a promising tool for infection imaging. In contrast, retention of the radioactivity in the blood was observed for [⁶⁸Ga]Ga-FRH. In conclusion, the stereoisomerism of potential radiotracers should be considered, as even minor structural differences can influence their pharmacokinetics and, consequently, the results of PET imaging.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"9 1","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ejnmmipharmchem.springeropen.com/counter/pdf/10.1186/s41181-024-00249-z","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140020602","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":"A novel PET probe to selectively image heat shock protein 90α/β isoforms in the brain","authors":"Takayuki Sakai,&nbsp;Aya Ogata,&nbsp;Hiroshi Ikenuma,&nbsp;Takashi Yamada,&nbsp;Saori Hattori,&nbsp;Junichiro Abe,&nbsp;Shinichi Imamura,&nbsp;Masanori Ichise,&nbsp;Mari Tada,&nbsp;Akiyoshi Kakita,&nbsp;Hiroko Koyama,&nbsp;Masaaki Suzuki,&nbsp;Takashi Kato,&nbsp;Kengo Ito,&nbsp;Yasuyuki Kimura","doi":"10.1186/s41181-024-00248-0","DOIUrl":"10.1186/s41181-024-00248-0","url":null,"abstract":"<div><h3>Background</h3><p>Heat shock proteins (HSPs) are present throughout the brain. They function as molecular chaperones, meaning they help with the folding and unfolding of large protein complexes. These chaperones are vital in the development of neuropathological conditions such as Alzheimer’s disease and Lewy body disease, with HSP90, a specific subtype of HSP, playing a key role. Many studies have shown that drugs that inhibit HSP90 activity have beneficial effects in the neurodegenerative diseases. Therefore, HSP90 PET imaging ligand can be used effectively to study HSP90 in neurodegenerative diseases. Among four HSP90 isoforms, two cytosolic isoforms (HSP90α and HSP90β) thought to be involved in the structural homeostasis of the proteins related to the neurodegenerative diseases. Currently, no useful PET imaging ligands selectively targeting the two cytosolic isoforms of HSP90 have been available yet.</p><h3>Results</h3><p>In this study, we developed a novel positron emission tomography (PET) imaging ligand, [¹¹C]BIIB021, by ¹¹C-radiolabeling (a positron emitter with a half-life of 20.4 min) 6-Chloro-9-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-9<i>H</i>-purin-2-amine (BIIB021), an inhibitor with a high affinity for and selectivity to HSP90α and HSP90β. [¹¹C]BIIB021 was synthesized with a high yield, molar activity and radiochemical purity. [¹¹C]BIIB021 showed a high binding affinity for rat brain homogenate as well as human recombinant HSP90α and HSP90β proteins. Radioactivity was well detected in the rat brain (SUV 1.4). It showed clear specific binding in PET imaging of healthy rats and autoradiography of healthy rat and human brain sections. Radiometabolite was detected in the brain, however, total distribution volume was well quantified using dual-input graphical model. Inhibition of p-glycoprotein increased brain radioactivity concentrations. However, total distribution volume values with and without p-glycoprotein inhibition were nearly the same.</p><h3>Conclusions</h3><p>We have developed a new PET imaging agent, [¹¹C]BIIB021, specifically targeting HSP90α/β. We have been successful in synthesizing [¹¹C]BIIB021 and in vitro and in vivo imaging HSP90α/β. However, the quantification of HSP90α/β is complicated by the presence of radiometabolites in the brain and the potential to be a substrate for p-glycoprotein. Further efforts are needed to develop radioligand suitable for imaging of HSP90α/β.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"9 1","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ejnmmipharmchem.springeropen.com/counter/pdf/10.1186/s41181-024-00248-0","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140020601","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":"Neopentyl glycol-based radiohalogen-labeled amino acid derivatives for cancer radiotheranostics","authors":"Yuta Kaizuka,&nbsp;Hiroyuki Suzuki,&nbsp;Tadashi Watabe,&nbsp;Kazuhiro Ooe,&nbsp;Atsushi Toyoshima,&nbsp;Kazuhiro Takahashi,&nbsp;Koichi Sawada,&nbsp;Takashi Iimori,&nbsp;Yoshitada Masuda,&nbsp;Takashi Uno,&nbsp;Kento Kannaka,&nbsp;Tomoya Uehara","doi":"10.1186/s41181-024-00244-4","DOIUrl":"10.1186/s41181-024-00244-4","url":null,"abstract":"<div><h3>Background</h3><p>L-type amino acid transporter 1 (LAT1) is overexpressed in various cancers; therefore, radiohalogen-labeled amino acid derivatives targeting LAT1 have emerged as promising candidates for cancer radiotheranostics. However, ²¹¹At-labeled amino acid derivatives exhibit instability against deastatination in vivo, making it challenging to use ²¹¹At for radiotherapy. In this study, radiohalogen-labeled amino acid derivatives with high dehalogenation stability were developed.</p><h3>Results</h3><p>We designed and synthesized new radiohalogen-labeled amino acid derivatives ([²¹¹At]At-NpGT, [¹²⁵I]I-NpGT, and [¹⁸F]F-NpGT) in which L-tyrosine was introduced into the neopentyl glycol (NpG) structure. The radiolabeled amino acid derivatives were recognized as substrates of LAT1 in the in vitro studies using C6 glioma cells. In a biodistribution study using C6 glioma-bearing mice, these agents exhibited high stability against in vivo dehalogenation and similar biodistributions. The similarity of [²¹¹At]At-NpGT and [¹⁸F]F-NpGT indicated that these pairs of radiolabeled compounds would be helpful in radiotheranostics. Moreover, [²¹¹At]At-NpGT exhibited a dose-dependent inhibitory effect on the growth of C6 glioma-bearing mice.</p><h3>Conclusions</h3><p>[²¹¹At]At-NpGT exhibited a dose-dependent inhibitory effect on the tumor growth of glioma-bearing mice, and its biodistribution was similar to that of other radiohalogen-labeled amino acid derivatives. These findings suggest that radiotheranostics using [¹⁸F]F-NpGT and [^123/131I]I-NpGT for diagnostic applications and [²¹¹At]At-NpGT and [¹³¹I]I-NpGT for therapeutic applications are promising.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"9 1","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ejnmmipharmchem.springeropen.com/counter/pdf/10.1186/s41181-024-00244-4","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139967674","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 comparison of [177Lu]Lu-rhPSMA-10.1 and [177Lu]Lu-rhPSMA-10.2 for endoradiotherapy of prostate cancer: biodistribution and dosimetry studies","authors":"Alexander Wurzer,&nbsp;Francesco De Rose,&nbsp;Sebastian Fischer,&nbsp;Markus Schwaiger,&nbsp;Wolfgang Weber,&nbsp;Stephan Nekolla,&nbsp;Hans-Jürgen Wester,&nbsp;Matthias Eiber,&nbsp;Calogero D’Alessandria","doi":"10.1186/s41181-024-00246-2","DOIUrl":"10.1186/s41181-024-00246-2","url":null,"abstract":"<div><h3>Background</h3><p>Radiohybrid PSMA-targeted ligands (rhPSMA) have been introduced as a novel platform for theranostic applications. Among a variety of rhPSMA-ligands developed for radioligand therapy, two stereoisomers [¹⁷⁷Lu]Lu-rhPSMA-10.1 and -10.2 have been synthesized and initially characterized in preclinical experiments with the aim to provide an optimized binding profile to human serum albumin, a reduction of charge, and thus accelerated kidney excretion, and unaffected or even improved tumor uptake. As both isomers showed similar in vitro characteristics and tumor uptake at 24 h post injection in tumor bearing mice and in order to identify the isomer with the most favorable pharmacokinetics for radioligand therapy, we carried out in-depth biodistribution and dosimetry studies in tumor-bearing and healthy mice.</p><h3>Results</h3><p>rhPSMA-10.1 and -10.2 were radiolabeled with lutetium-177 according to the established procedures of other DOTA-based PSMA ligands and displayed a high and comparable stability in all buffers and human serum (&gt; 97%, 24 h). Biodistribution studies revealed fast clearance from the blood pool (0.3–0.6%ID/g at 1 h) and other background tissues within 48 h. Distinctive differences were found in the kidneys, where [¹⁷⁷Lu]Lu-rhPSMA-10.1 displayed lower initial uptake and faster excretion kinetics compared to [¹⁷⁷Lu]Lu-rhPSMA-10.2 expressed by a 1.5-fold and ninefold lower uptake value at 1 h and 24 h in healthy animals, respectively. Tumor uptake was comparable and in the range of 8.6–11.6%ID/g for both isomers over 24 h and was maintained up to 168 h at a level of 2.2 ± 0.8 and 4.1 ± 1.4%ID/g for [¹⁷⁷Lu]Lu-rhPSMA-10.1 and [¹⁷⁷Lu]Lu-rhPSMA-10.2, respectively.</p><h3>Conclusion</h3><p>Our preclinical data on biodistribution and dosimetry indicate a more favorable profile of [¹⁷⁷Lu]Lu-rhPSMA-10.1 compared to [¹⁷⁷Lu]Lu-rhPSMA-10.2 for PSMA-targeted radioligand therapy. [¹⁷⁷Lu]Lu-rhPSMA-10.1 shows fast kidney clearance kinetics resulting in excellent tumor-to-organ ratios over a therapy relevant time course. Meanwhile, [¹⁷⁷Lu]Lu-rhPSMA-10.1 is currently being investigated in clinical phase I/II studies in patients with mCRPC (NCT05413850), in patients with high-risk localized PC (NCT06066437, Nautilus Trial) and after external beam radiotherapy (NCT06105918).</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"9 1","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ejnmmipharmchem.springeropen.com/counter/pdf/10.1186/s41181-024-00246-2","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139968223","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}