EJNMMI Radiopharmacy and Chemistry最新文献

{"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}

{"title":"Optimization and scale up of production of the PSMA imaging agent [18F]AlF-P16-093 on a custom automated radiosynthesis platform","authors":"David Alexoff,&nbsp;Seok Rye Choi,&nbsp;Karl Ploessl,&nbsp;Dohyun Kim,&nbsp;Ruiyue Zhao,&nbsp;Lin Zhu,&nbsp;Hank Kung","doi":"10.1186/s41181-024-00247-1","DOIUrl":"10.1186/s41181-024-00247-1","url":null,"abstract":"<div><h3>Background</h3><p>Recent advancements in positron emission tomograph (PET) using prostate specific membrane antigen (PSMA)-targeted radiopharmaceuticals have changed the standard of care for prostate cancer patients by providing more accurate information during staging of primary and recurrent disease. [⁶⁸Ga]Ga-P16-093 is a new PSMA-PET radiopharmaceutical that demonstrated superior imaging performance in recent head-to-head studies with [⁶⁸Ga]Ga-PSMA-11. To improve the availability of this new PSMA PET imaging agent, [¹⁸F]AlF-P16-093 was developed. The ¹⁸F-analog [¹⁸F]AlF-P16-093 has been synthesized manually at low activity levels using [¹⁸F]AlF²⁺ and validated in pre-clinical models. This work reports the optimization of the production of &gt; 15 GBq of [¹⁸F]AlF-P16-093 using a custom automated synthesis platform.</p><h3>Results</h3><p>The sensitivity of the radiochemical yield of [¹⁸F]AlF-P16-093 to reaction parameters of time, temperature and reagent amounts was investigated using a custom automated system. The automated system is a low-cost, cassette-based system designed for 1-pot syntheses with flow-controlled solid phase extraction (SPE) workup and is based on the Raspberry Pi Zero 2 microcomputer/Python3 ecosystem. The optimized none-decay-corrected yield was 52 ± 4% (N = 3; 17.5 ± 2.2 GBq) with a molar activity of 109 ± 14 GBq/µmole and a radiochemical purity of 98.6 ± 0.6%. Run time was 30 min. A two-step sequence was used: SPE-purified [¹⁸F]F⁻ was reacted with 80 nmoles of freeze-dried AlCl₃·6H₂O at 65 °C for 5 min followed by reaction with 160 nmoles of P16-093 ligand at 40 °C for 4 min in a 1:1 mixture of ethanol:0.5 M pH 4.5 NaOAc buffer. The mixture was purified by SPE (&gt; 97% recovery). The final product formulation (5 mM pH 7 phosphate buffer with saline) exhibited a rate of decline in radiochemical purity of ~ 1.4%/h which was slowed to ~ 0.4%/h when stored at 4 °C.</p><h3>Conclusion</h3><p>The optimized method using a custom automated system enabled the efficient (&gt; 50% none-decay-corrected yield) production of [¹⁸F]AlF-P16-093 with high radiochemical purity (&gt; 95%). The method and automation system are simple and robust, facilitating further clinical studies with [¹⁸F]AlF-P16-093.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"9 1","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ejnmmipharmchem.springeropen.com/counter/pdf/10.1186/s41181-024-00247-1","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139929414","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":"Radiosynthesis, structural identification and in vitro tissue binding study of [18F]FNA-S-ACooP, a novel radiopeptide for targeted PET imaging of fatty acid binding protein 3","authors":"Pyry Dillemuth,&nbsp;Tuomas Karskela,&nbsp;Abiodun Ayo,&nbsp;Jesse Ponkamo,&nbsp;Jonne Kunnas,&nbsp;Johan Rajander,&nbsp;Olli Tynninen,&nbsp;Anne Roivainen,&nbsp;Pirjo Laakkonen,&nbsp;Anu J. Airaksinen,&nbsp;Xiang-Guo Li","doi":"10.1186/s41181-024-00245-3","DOIUrl":"10.1186/s41181-024-00245-3","url":null,"abstract":"<div><h3>Background</h3><p>Fatty acid binding protein 3 (FABP3) is a target with clinical relevance and the peptide ligand ACooP has been identified for FABP3 targeting. ACooP is a linear decapeptide containing a free amino and thiol group, which provides opportunities for conjugation. This work is to develop methods for radiolabeling of ACooP with fluorine-18 (¹⁸F) for positron emission tomography (PET) applications, and evaluate the binding of the radiolabeled ACooP in human tumor tissue sections with high FABP3 expression.</p><h3>Results</h3><p>The prosthetic compound 6-[¹⁸F]fluoronicotinic acid 4-nitrophenyl ester was conveniently prepared with an on-resin ¹⁸F-fluorination in 29.9% radiochemical yield and 96.6% radiochemical purity. Interestingly, 6-[¹⁸F]fluoronicotinic acid 4-nitrophenyl ester conjugated to ACooP exclusively by <i>S</i>-acylation instead of the expected <i>N</i>-acylation, and the chemical identity of the product [¹⁸F]FNA-<i>S</i>-ACooP was confirmed. In the in vitro binding experiments, [¹⁸F]FNA-<i>S</i>-ACooP exhibited heterogeneous and high focal binding in malignant tissue sections, where we also observed abundant FABP3 positivity by immunofluorescence staining. Blocking study further confirmed the [¹⁸F]FNA-<i>S</i>-ACooP binding specificity.</p><h3>Conclusions</h3><p>FABP3 targeted ACooP peptide was successfully radiolabeled by <i>S</i>-acylation using 6-[¹⁸F]fluoronicotinic acid 4-nitrophenyl ester as the prosthetic compound. The tissue binding and blocking studies together with anti-FABP3 immunostaining confirmed [¹⁸F]FNA-<i>S</i>-ACooP binding specificity. Further preclinical studies of [¹⁸F]FNA-<i>S</i>-ACooP are warranted.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"9 1","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ejnmmipharmchem.springeropen.com/counter/pdf/10.1186/s41181-024-00245-3","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139929415","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":"Chelator impact: investigating the pharmacokinetic behavior of copper-64 labeled PD-L1 radioligands","authors":"Fabian Krutzek,&nbsp;Cornelius K. Donat,&nbsp;Sven Stadlbauer","doi":"10.1186/s41181-024-00243-5","DOIUrl":"10.1186/s41181-024-00243-5","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;p&gt;Programmed cell death ligand 1 (PD-L1) plays a critical role in the tumor microenvironment and overexpression in several solid cancers has been reported. This was associated with a downregulation of the local immune response, specifically of T-cells. Immune checkpoint inhibitors showed a potential to break this localized immune paralysis, but only 30% of patients are considered responders. New diagnostic approaches are therefore needed to determine patient eligibility. Small molecule radiotracers targeting PD-L1, may serve as such diagnostic tools, addressing the heterogeneous PD-L1 expression between and within tumor lesions, thus aiding in therapy decisions.&lt;/p&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;p&gt;Four biphenyl-based small-molecule PD-L1 ligands were synthesized using a convergent synthetic route with a linear sequence of up to eleven steps. As a chelator NODA-GA, CB-TE2A or DiAmSar was used to allow radiolabeling with copper-64 ([&lt;sup&gt;64&lt;/sup&gt;Cu]Cu-&lt;b&gt;14&lt;/b&gt;–[&lt;sup&gt;64&lt;/sup&gt;Cu]Cu-&lt;b&gt;16&lt;/b&gt;). In addition, a dimeric structure based on DiAmSar was synthesized ([&lt;sup&gt;64&lt;/sup&gt;Cu]Cu-&lt;b&gt;17&lt;/b&gt;). All four radioligands exhibited high proteolytic stability (&gt; 95%) up to 48 h post-radiolabeling. Saturation binding yielded moderate affinities toward PD-L1, ranging from 100 to 265 nM. Real-time radioligand binding provided more promising &lt;i&gt;K&lt;/i&gt;&lt;sub&gt;D&lt;/sub&gt; values around 20 nM for [&lt;sup&gt;64&lt;/sup&gt;Cu]Cu-&lt;b&gt;14&lt;/b&gt; and [&lt;sup&gt;64&lt;/sup&gt;Cu]Cu-&lt;b&gt;15&lt;/b&gt;. In vivo PET imaging in mice bearing both PC3 PD-L1 overexpressing and PD-L1-mock tumors was performed at 0–2, 4–5 and 24–25 h post injection (p.i.). This revealed considerably different pharmacokinetic profiles, depending on the substituted chelator. [&lt;sup&gt;64&lt;/sup&gt;Cu]Cu-&lt;b&gt;14&lt;/b&gt;, substituted with NODA-GA, showed renal clearance with low liver uptake, whereas substitution with the cross-bridged cyclam chelator CB-TE2A resulted in a primarily hepatobiliary clearance. Notably, the monomeric DiAmSar radioligand [&lt;sup&gt;64&lt;/sup&gt;Cu]Cu-&lt;b&gt;16&lt;/b&gt; demonstrated a higher liver uptake than [&lt;sup&gt;64&lt;/sup&gt;Cu]Cu-&lt;b&gt;15&lt;/b&gt;, but was still renally cleared as evidenced by the lack of uptake in gall bladder and intestines. The dimeric structure [&lt;sup&gt;64&lt;/sup&gt;Cu]Cu-&lt;b&gt;17&lt;/b&gt; showed extensive accumulation and trapping in the liver but was also cleared via the renal pathway. Of all tracer candidates and across all timepoints, [&lt;sup&gt;64&lt;/sup&gt;Cu]Cu-&lt;b&gt;17&lt;/b&gt; showed the highest accumulation at 24 h p.i. in the PD-L1-overexpressing tumor of all timepoints and all radiotracers, indicating drastically increased circulation time upon dimerization of two PD-L1 binding motifs.&lt;/p&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;p&gt;This study shows that chelator choice significantly influences the pharmacokinetic profile of biphenyl-based small molecule PD-L1 radioligands. The NODA-GA-conjugated radioligand [&lt;sup&gt;64&lt;/sup&gt;Cu]Cu-&lt;b&gt;14&lt;/b&gt; exhibited favorable renal clearance; however, the limited uptake in tumors suggests the need for structural modifications to the bind","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"9 1","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ejnmmipharmchem.springeropen.com/counter/pdf/10.1186/s41181-024-00243-5","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139899167","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preclinical evaluation of new GRPR-antagonists with improved metabolic stability for radiotheranostic use in oncology","authors":"Panagiotis Kanellopoulos,&nbsp;Adam Mattsson,&nbsp;Ayman Abouzayed,&nbsp;Karim Obeid,&nbsp;Berthold A. Nock,&nbsp;Vladimir Tolmachev,&nbsp;Theodosia Maina,&nbsp;Anna Orlova","doi":"10.1186/s41181-024-00242-6","DOIUrl":"10.1186/s41181-024-00242-6","url":null,"abstract":"<div><h3>Background</h3><p>The gastrin-releasing peptide receptor (GRPR) has been extensively studied as a biomolecular target for peptide-based radiotheranostics. However, the lack of metabolic stability and the rapid clearance of peptide radioligands, including radiolabeled GRPR-antagonists, often impede clinical application. Aiming at circumventing these drawbacks, we have designed three new GRPR-antagonist radioligands using [^99mTc]Tc-DB15 ([^99mTc]Tc-N₄-AMA-DIG-_DPhe-Gln-Trp-Ala-Val-Sar-His-Leu-NHEt; AMA: <i>p</i>-aminomethylaniline; DIG: diglycolate) as a motif, due to its high GRPR-affinity and stability to neprilysin (NEP). The new analogues carry the DOTAGA-chelator (1,4,7,10-tetraazacyclododecane-1-glutaric acid-4,7,10-triacetic acid) through different linkers at the N-terminus to allow for labeling with the theranostic radionuclide pair In-111/Lu-177. After labeling with In-111 the following radioligands were evaluated: (i) [¹¹¹In]In-AU-SAR-M1 ([¹¹¹In]In-DOTAGA-AMA-DIG-_DPhe-Gln-Trp-Ala-Val-Sar-His-Leu-NHEt), (ii) [¹¹¹In]In-AU-SAR-M2 ([¹¹¹In]In-[DOTAGA-Arg]AU-SAR-M1) and (iii) [¹¹¹In]In-AU-SAR-M3 ([¹¹¹In]In-[DOTAGA-_DArg]AU-SAR-M1).</p><h3>Results</h3><p>These radioligands were compared in a series of in vitro assays using prostate adenocarcinoma PC-3 cells and in murine models. They all displayed high and GRPR-specific uptake in PC-3 cells. Analysis of mice blood collected 5 min post-injection (pi) revealed similar or even higher metabolic stability of the new radioligands compared with [^99mTc]Tc-DB15. The stability could be further increased when the mice were treated with Entresto® to in situ induce NEP-inhibition. In PC-3 xenograft-bearing mice, [¹¹¹In]In-AU-SAR-M1 displayed the most favourable biodistribution profile, combining a good tumor retention with the highest tumor-to-organ ratios, with the kidneys as the dose-limiting organ.</p><h3>Conclusions</h3><p>These findings strongly point at AU-SAR-M1 as a promising radiotherapeutic candidate when labeled with Lu-177, or other medically appealing therapeutic radiometals, especially when combined with in situ NEP-inhibition. To this goal further investigations are currently pursued.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"9 1","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ejnmmipharmchem.springeropen.com/counter/pdf/10.1186/s41181-024-00242-6","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139745767","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":"Intranasal administration enhances size-dependent pulmonary phagocytic uptake of poly(lactic-co-glycolic acid) nanoparticles","authors":"Seung Ho Baek,&nbsp;Eun-Ha Hwang,&nbsp;Gyeung Haeng Hur,&nbsp;Green Kim,&nbsp;You Jung An,&nbsp;Jae-Hak Park,&nbsp;Jung Joo Hong","doi":"10.1186/s41181-023-00227-x","DOIUrl":"10.1186/s41181-023-00227-x","url":null,"abstract":"<div><h3>Background</h3><p>Nanoparticles exhibit distinct behaviours within the body, depending on their physicochemical properties and administration routes. However, in vivo behaviour of poly(lactic-<i>co</i>-glycolic acid) (PLGA) nanoparticles, especially when administered nasally, remains unexplored; furthermore, there is a lack of comparative analysis of uptake efficiency among different administration routes. Therefore, here, we aimed to comprehensively investigate the real-time in vivo behaviour of PLGA nanoparticles across various administration routes. PLGA-NH₂ nanoparticles of three sizes were synthesised using an oil-in-water single-emulsion method. We assessed their uptake by murine macrophage RAW264.7 cells using fluorescence microscopy. To enable real-time tracking, we conjugated p-SCN-Bn-deferoxamine to PLGA-NH₂ nanoparticles and further radiolabelled them with ⁸⁹Zr-oxalate before administration to mice via different routes. Nanoparticle internalisation by lung immune cells was monitored using fluorescence-activated cell sorting analysis.</p><h3>Results</h3><p>The nanoparticle sizes were 294 ± 2.1 (small), 522.5 ± 5.58 (intermediate), and 850 ± 18.52 nm (large). Fluorescent labelling did not significantly alter the nanoparticle size and charge. The level of uptake of small and large nanoparticles by RAW264.7 cells was similar, with phagocytosis inhibition primarily reducing the internalisation of large particles. Positron emission tomography revealed that intranasal delivery resulted in the highest and most targeted pulmonary uptake, whereas intravenous administration led to accumulation mainly in the liver and spleen. Nasal delivery of large nanoparticles resulted in enhanced uptake by myeloid immune cells relative to lymphoid cells, whereas dendritic cell uptake initially peaked but declined over time.</p><h3>Conclusions</h3><p>Our study provides valuable insights into advancing nanomedicine and drug delivery, with the potential for expanding the clinical applications of nanoparticles.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"9 1","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ejnmmipharmchem.springeropen.com/counter/pdf/10.1186/s41181-023-00227-x","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139734158","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}