EJNMMI Radiopharmacy and Chemistry最新文献

{"title":"Rapid cleavage of 6-[18F]fluoronicotinic acid prosthetic group governs BT12 glioblastoma xenograft uptake: implications for radiolabeling design of biomolecules","authors":"Pyry Dillemuth,&nbsp;Abiodun Ayo,&nbsp;Xiaoqing Zhuang,&nbsp;Petter Lövdahl,&nbsp;Heidi Liljenbäck,&nbsp;Salli Kärnä,&nbsp;Tatsiana Auchynnikava,&nbsp;Jonne Kunnas,&nbsp;Jesse Ponkamo,&nbsp;Maxwell W. G. Miner,&nbsp;Johan Rajander,&nbsp;Jessica M. Rosenholm,&nbsp;Anne Roivainen,&nbsp;Anu J. Airaksinen,&nbsp;Pirjo Laakkonen,&nbsp;Xiang-Guo Li","doi":"10.1186/s41181-025-00368-1","DOIUrl":"10.1186/s41181-025-00368-1","url":null,"abstract":"<div><h3>Background</h3><p>Peptides radiolabeled with fluorine-18 are frequently synthesized using prosthetic groups. Among them, activated esters of 6-[¹⁸F]fluoronicotinic acid ([¹⁸F]FNA) have been prepared and successfully employed for ¹⁸F-labeling of diverse biomolecules, including peptides. The utility of [¹⁸F]FNA as a prosthetic compound has been demonstrated in both preclinical and clinical settings, including radiopharmaceuticals targeting prostate-specific membrane antigen and poly(ADP ribose) polymerase inhibitors. This study aims to evaluate a [¹⁸F]FNA-conjugated nonapeptide, [¹⁸F]FNA-<i>N</i>-CooP, for positron emission tomography imaging of intracranial BT12 glioblastoma xenografts in a mouse model. Additionally, this study highlights the importance of including control experiments with prosthetic compound alone when it constitutes a major radiometabolite.</p><h3>Results</h3><p>[¹⁸F]FNA-<i>N</i>-CooP successfully delineated intracranial glioblastoma xenografts yielding a standardized uptake value of 0.21 ± 0.03 (<i>n</i> = 4) and a tumor-to-brain ratio of 1.84 ± 0.29. Ex vivo autoradiography of tumor tissue showed a partial co-localization between radioactivity uptake and the target fatty acid binding protein 3 expression. However, in vivo instability of [¹⁸F]FNA-<i>N</i>-CooP was observed, with [¹⁸F]FNA identified as a major radiometabolite. Notably, control studies using [¹⁸F]FNA alone also visualized tumors, producing a standardized uptake value of 0.90 ± 0.10 (<i>n</i> = 4) and a tumor-to-brain ratio of 1.51 ± 0.08.</p><h3>Conclusions</h3><p>Both [¹⁸F]FNA-<i>N</i>-CooP and [¹⁸F]FNA enabled PET visualization of human glioblastoma in the mouse model. However, the prominent presence of [¹⁸F]FNA as radiometabolite complicates the interpretation of [¹⁸F]FNA-<i>N</i>-CooP PET data, suggesting that the observed radioactivity uptake may primarily originate from [¹⁸F]FNA and other radiometabolites. Enhancing peptide stability is essential for improving imaging specificity. This study underscores the critical need to assess the imaging contributions of prosthetic groups when they function as significant radiometabolites.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"10 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12238435/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144590102","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of new albumin-binding radiotracers for PET imaging of cerebrospinal fluid flow in the glymphatic system","authors":"Martta Peltoniemi,&nbsp;Surachet Imlimthan,&nbsp;Sonja C. Jalonen,&nbsp;Niklas Daniel Åke Persson,&nbsp;Terhi J. Lohela,&nbsp;Tuomas O. Lilius,&nbsp;Mirkka Sarparanta","doi":"10.1186/s41181-025-00365-4","DOIUrl":"10.1186/s41181-025-00365-4","url":null,"abstract":"<div><h3>Background</h3><p>The glymphatic system is a recently discovered brain-wide clearance system that allows the cerebrospinal fluid (CSF) flow to clear metabolic waste, but the tools for the quantitative and non-invasive investigation of its function and activity especially in humans is lacking, hindering studies on glymphatic system physiology and therapeutic potential of glymphatic drug delivery and modulation. We postulated that albumin-binding radiotracers could be used to this end by binding to the endogenous protein in CSF, constituting a macromolecular, biological radiotracer, allowing for the visualization of CSF flow in the central nervous system non-invasively with positron emission tomography (PET). </p><h3>Results</h3><p>We prepared three albumin-binding tracers based on 4-(p-iodophenyl)butyric acid and truncated Evans Blue radiolabeled with gallium-68 using the NODAGA chelator for in vivo radiolabeling of CSF albumin, and an in vitro radiolabeled reference tracer Al[¹⁸F]F-RESCA-rat serum albumin (RSA) with high radiochemical yield and purity, and acceptable molar activity (A_m). The biological evaluation of the tracers showed high radiolabel stability and rapid binding with albumin in vitro and in vivo with the biological half-life in Swiss mice after intravenous administration matching serum albumin (&gt; 18 h). Dynamic PET imaging in female Sprague Dawley rats under ketamine/dexmedetomidine anesthesia after lumbar and intracisternal infusion showed distribution of the tracers towards intracranial space and along the spinal canal from the infusion site. However, the cervical lymph nodes were only visualized after the infusion of Al[¹⁸F]F-RESCA-RSA, characteristic for macromolecular tracers, indicating that the gallium-68-labeled tracers did not bind fully to endogenous CSF albumin in vivo, but were distributing to different brain areas according to their physicochemical properties.</p><h3>Conclusions</h3><p>While the relatively low molar activity (A_m) of the [⁶⁸Ga]Ga-NODAGA complex achieved in our setup combined with the limited amount of endogenous albumin at the infusion site (0.012–0.024 nmol) resulted in residual unbound tracer in the rat CSF in vivo, the tracers, especially the Al[¹⁸F]F-RESCA-RSA show promise for tracking CSF flow with PET, constituting the first tailored radiotracers to this end.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"10 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12229972/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144566912","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of a CYP11B2 imaging tracer for primary aldosteronism: basic evaluation of iodine- and fluorine-incorporated pyridinyldihydroquinolinone derivatives","authors":"Yusuke Yagi,&nbsp;Hiroyuki Kimura,&nbsp;Riko Fuseda,&nbsp;Takaaki Murakami,&nbsp;Marina Omokawa,&nbsp;Kaito Ohta,&nbsp;Satoko Kise,&nbsp;Masakatsu Sone,&nbsp;Hiroyuki Yasui,&nbsp;Nobuya Inagaki,&nbsp;Hideo Saji","doi":"10.1186/s41181-025-00361-8","DOIUrl":"10.1186/s41181-025-00361-8","url":null,"abstract":"<div><h3>Background</h3><p>Current methods for diagnosing primary aldosteronism (PA) are limited by their invasiveness and diagnostic accuracy. This study aimed to develop nuclear medicine imaging tracers targeting CYP11B2, which is overexpressed in patients with PA.</p><h3>Results</h3><p>We successfully synthesized iodinated and fluoroethoxynated pyridinyldihydroquinolinone (PDHQ) derivatives, among which PDHQ-1 exhibited the highest selectivity for CYP11B2. Furthermore, [¹²⁵I]PDHQ-1 accumulated in the adrenal gland soon after administration, reaching its highest saturation compared to that in other organs 5 min after administration; however, its radioactivity decreased over time. Autoradiographic analysis revealed that [¹²⁵I]PDHQ-1 displayed a 4.4-fold higher accumulation in the CYP11B2 region of adrenal sections from human patients with aldosterone-producing adenomas than in the CYP11B1 region. In contrast, [¹²⁵I]IMTO, which is a highly specific radiotracer for imaging adrenocortical tissue, displayed similar accumulation in the CYP11B2 and CYP11B1 regions.</p><h3>Conclusions</h3><p>Collectively, our results suggest that [¹²⁵I]PDHQ-1, featuring a pyridinyldihydroquinolinone scaffold, shows potential as an imaging tracer for PA.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"10 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12229973/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144566911","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":"Cancer in translation: cyanine carborane salts: a multifunctional theranostic approach to cancer treatment","authors":"Simran Deep Kaur,&nbsp;Deepak N. Kapoor","doi":"10.1186/s41181-025-00360-9","DOIUrl":"10.1186/s41181-025-00360-9","url":null,"abstract":"","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"10 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12229371/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144551607","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":"Exploring the radiochemistry of PARP inhibitors: a new era in therapy and imaging","authors":"Gianluca Destro,&nbsp;Rebecca Rizzo,&nbsp;Chiara Rua,&nbsp;Raha Rouhbakhsh Azimi,&nbsp;Silvia Morbelli","doi":"10.1186/s41181-025-00364-5","DOIUrl":"10.1186/s41181-025-00364-5","url":null,"abstract":"<div><h3>Background</h3><p>Poly (ADP-ribose) polymerase (PARP) inhibitors have emerged as a promising class of therapeutics, particularly in the treatment of cancers with defective DNA repair mechanisms, such as those with breast cancer genes (BRCA) mutations. Their effectiveness in cancer therapy is now well-established, but the ongoing advancements in radiochemistry are expanding their potential to combine both therapeutic and imaging capabilities. Radiolabelled PARP inhibitors, used in conjunction with positron emission tomography (PET) or single-photon emission computed tomography (SPECT), might enable precise imaging of PARP expression in tumours, potentially providing invaluable insights into treatment response, tumor heterogeneity, and molecular profiling.</p><h3>Main body</h3><p>The radiochemistry of PARP inhibitors involves incorporating radioisotopes (most of all Fluorine-18) into the molecular structure of these molecules. The first strategy used to achieve this goal was the use of prosthetic groups bearing the fluorine-18. Then, the development of radioisotopologue have gained ground, followed later by the replacement with other halogens such as bromine, iodine, or astatine has taken place. Another frontier is represented by the metal radiolabelling of these inhibitors through the introduction of a chelator moiety to these molecules, thus further expanding both imaging and therapy applications.</p><h3>Conclusion</h3><p>Finally, emerging evidence suggest the possibility to involve PARP-related radiopharmaceuticals in theranostics approaches. Despite challenges such as the complexity of radiolabelling, regulatory hurdles, and the need for more robust clinical validation, the continued exploration of the radiochemistry of PARP inhibitors promises to revolutionize both the diagnosis and treatment of cancer, offering hope for more effective and personalized cancer care.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"10 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12229409/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144551608","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":"Pyridyl-Ala in the third position of radiolabeled somatostatin antagonists: the effect of regioisomeric substitution","authors":"Rosalba Mansi,&nbsp;Natalie Bertarelli,&nbsp;Luigi Del Pozzo,&nbsp;Sandra Zanger,&nbsp;Tais Basaco Bernabeu,&nbsp;Helmut Maecke,&nbsp;Melpomeni Fani","doi":"10.1186/s41181-025-00363-6","DOIUrl":"10.1186/s41181-025-00363-6","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;p&gt;The radiolabeled somatostatin receptor subtype 2 (SST&lt;sub&gt;2&lt;/sub&gt;) antagonists LM3 (Phe(4-Cl)&lt;sup&gt;1&lt;/sup&gt;‐c(&lt;span&gt;d&lt;/span&gt;Cys&lt;sup&gt;2&lt;/sup&gt;‐Tyr&lt;sup&gt;3&lt;/sup&gt;‐&lt;span&gt;d&lt;/span&gt;Aph(Cbm)&lt;sup&gt;4&lt;/sup&gt;‐Lys&lt;sup&gt;5&lt;/sup&gt;‐Thr&lt;sup&gt;6&lt;/sup&gt;‐Cys&lt;sup&gt;7&lt;/sup&gt;)-&lt;span&gt;d&lt;/span&gt;Tyr&lt;sup&gt;8&lt;/sup&gt;-NH&lt;sub&gt;2&lt;/sub&gt;) and JR11 (Phe(4-Cl)&lt;sup&gt;1&lt;/sup&gt;‐c(&lt;span&gt;d&lt;/span&gt;Cys&lt;sup&gt;2&lt;/sup&gt;‐Aph(Hor)&lt;sup&gt;3&lt;/sup&gt;‐&lt;span&gt;d&lt;/span&gt;Aph(Cbm)&lt;sup&gt;4&lt;/sup&gt;‐Lys&lt;sup&gt;5&lt;/sup&gt;‐Thr&lt;sup&gt;6&lt;/sup&gt;‐Cys&lt;sup&gt;7&lt;/sup&gt;)-&lt;span&gt;d&lt;/span&gt;Tyr&lt;sup&gt;8&lt;/sup&gt;-NH&lt;sub&gt;2&lt;/sub&gt;) are under clinical evaluation for imaging and treatment of neuroendocrine tumors. These peptides differ at position 3, where LM3 contains Tyr&lt;sup&gt;3&lt;/sup&gt;, while JR11 incorporates Aph(Hor)&lt;sup&gt;3&lt;/sup&gt;. The amino acid at this position is crucial in the design of somatostatin ligands, agonists and antagonists, influencing affinity and receptor subtype specificity. Pyridylalanine, a nonnatural amino acid, presents three regioisomers 2-pyridylalanine (2Pal), 3-pyridylalanine (3Pal), and 4-pyridylalanine (4Pal), which differ only in the nitrogen atom’s position in the aromatic ring, allowing minimal chemical modification. We investigated whether the new somatostatin antagonists DOTA-[2Pal&lt;sup&gt;3&lt;/sup&gt;]-LM3, DOTA-[3Pal&lt;sup&gt;3&lt;/sup&gt;]-LM3 and DOTA-[4Pal&lt;sup&gt;3&lt;/sup&gt;]-LM3, radiolabeled with Lu-177, differ among them and how they compare with the clinically used [&lt;sup&gt;177&lt;/sup&gt;Lu]Lu-DOTA-LM3.&lt;/p&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;p&gt;The synthesis of the DOTA-[2Pal&lt;sup&gt;3&lt;/sup&gt;]-LM3 resulted in the formation of two diastereomers, with the &lt;span&gt;d&lt;/span&gt;2Pal derivative lacking receptor recognition and affinity, contrary to the enantiomer &lt;span&gt;l (l&lt;/span&gt;2Pal) derivative. The hydrophilicity of [&lt;sup&gt;177&lt;/sup&gt;Lu]Lu-DOTA-[xPal&lt;sup&gt;3&lt;/sup&gt;]-LM3 increased in the order of &lt;span&gt;l&lt;/span&gt;2Pal &lt; 3Pal &lt; 4Pal (log&lt;i&gt;D&lt;/i&gt; = -2.3 ± 0.1 -2.5 ± 0.1 and -2.6 ± 0.1, respectively), being similar or significantly higher than [&lt;sup&gt;177&lt;/sup&gt;Lu]Lu-DOTA-LM3 (log&lt;i&gt;D&lt;/i&gt; = -2.3 ± 0.1). Saturation binding studies indicated a trend of affinity improvement by &lt;span&gt;l&lt;/span&gt;2Pal &lt; 3Pal &lt; 4Pal (K&lt;sub&gt;D&lt;/sub&gt; = 0.18 ± 0.02, 0.15 ± 0.01 and 0.11 ± 0.01 nM, respectively), which is similar to [&lt;sup&gt;177&lt;/sup&gt;Lu]Lu-DOTA-LM3 (K&lt;sub&gt;D&lt;/sub&gt; = 0.09 ± 0.02 nM). Surprisingly, despite similar accumulation in SST&lt;sub&gt;2&lt;/sub&gt;-positive tumors, differences were observed in the body distribution. The hydrophilicity of the Pal amino acids is likely responsible for the higher kidney uptake of the three &lt;sup&gt;177&lt;/sup&gt;Lu-Pal-radioligands when compared to [&lt;sup&gt;177&lt;/sup&gt;Lu]Lu-DOTA-LM3. In particular, [&lt;sup&gt;177&lt;/sup&gt;Lu]Lu-DOTA-[3Pal&lt;sup&gt;3&lt;/sup&gt;]-LM3 is characterized by high uptake and long retention in kidneys, probably due to its high stability in renal tissue. Chromatographic analysis of kidney homogenates revealed that more than 60% of peptide remained intact 1 h after injection.&lt;/p&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;p&gt;Our study revealed that the replacement of Tyr&lt;sup&gt;3&lt;/sup&gt; with Pal&lt;sup&gt;3&lt;/sup&gt; isomers does no","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"10 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12214102/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144537578","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":"212Pb in targeted radionuclide therapy: a review","authors":"Jarred Michael Scaffidi-Muta,&nbsp;Andrew David Abell","doi":"10.1186/s41181-025-00362-7","DOIUrl":"10.1186/s41181-025-00362-7","url":null,"abstract":"<div><h3>Background</h3><p>The selective delivery of α-emitting radionuclides is emerging as a highly effective form of cancer therapy. With a short range and high cytotoxicity, α-particles can selectively kill cancerous cells whilst minimising harm to surrounding healthy tissue. As the parent of the α-emitter ²¹²Bi, ²¹²Pb has seen increasing therapeutic use on account of its favourable chemistry, half-life, and decay properties. This review comprehensively discusses the clinical development of ²¹²Pb in recent years, particularly its production, chelation chemistry, and therapeutic adoption.</p><h3>Main body</h3><p>Improvements in generator technology and supply have overcome the historically limited availability of ²¹²Pb, enabling a surge of research in the field. Numerous bifunctional chelators have since been developed, which enable facile conjugation of ²¹²Pb to a plethora of tumour targeting carriers. Advancements in nuclear imaging techniques, and the use ²⁰³Pb as an imaging surrogate, have enabled accurate biodistribution and dosimetry information to inform preclinical studies. These factors have attracted considerable commercial interest in ²¹²Pb, culminating in the rapid translation of this radionuclide into the clinic, where it is being investigated in the treatment of a range of malignancies.</p><h3>Conclusion</h3><p>Radiotherapy with ²¹²Pb has shown enormous promise in preclinical and clinical studies. While challenges still remain before ²¹²Pb can be more widely adopted, remarkable progress has been made in addressing these. At present, the therapeutic potential of ²¹²Pb is only beginning to be realised.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"10 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12214231/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144537665","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":"Structure–activity relationship of 18F-labeled PD-L1-targeting small molecule ligands: impact of radiolabeling strategy on affinity and in vivo performance","authors":"Fabian Krutzek,&nbsp;Cornelius K. Donat,&nbsp;Sven Stadlbauer","doi":"10.1186/s41181-025-00359-2","DOIUrl":"10.1186/s41181-025-00359-2","url":null,"abstract":"<div><h3>Background</h3><p>Immune checkpoint inhibitor therapy addressing the PD-1/PD-L1 axis is a promising approach in cancer treatment. A clinically suitable radiotracer would allow molecular imaging of the temporospatial changes in tumor PD-L1 expression. This could enable the clinicians to select eligible patients for checkpoint therapy and monitor therapeutic efficacy.</p><h3>Results</h3><p>Four biphenyl-based small-molecule PD-L1 ligands were synthesized using a convergent synthetic route, with a linear sequence of up to eleven steps. Two candidates were covalently labeled with ¹⁸F via either an azido glycosyl or PEG2 moiety, while the other two were modified with a RESCA chelator for Al[¹⁸F]F²⁺-labeling. The lipophilicity was assessed through determination of log <i>D</i>_7.4 values. In vitro binding affinities (inhibition constant, <i>K</i>_i) toward PD-L1 were determined in competition with one of our previously published biphenyl-based small-molecule (<i>K</i>_D =  ~ 21 nM). Compared to this compound, both covalently labeled ¹⁸F-ligands exhibited decreased water solubility (log <i>D</i>_7.4 ~ − 2.5 and − 2.7), along with a markedly reduced (<i>K</i>_i = 200‒500 nM) affinity. This was in line with in vivo small animal PET, where both compounds were characterized by a negligible tumor uptake, lack of contrast between target-positive/negative tumors and exclusively unfavorable hepatobiliary excretion. Similar results were observed for the chelator-modified ligands with slightly increased hydrophilicity (log <i>D</i>_7.4 ~ − 2.8 and − 2.9), showing a binding affinity of 150 nM for one compound, while binding was lost completely for the other. Again, a poor in vivo performance was observed, characterized by hepatobiliary clearance and lack of specific tumor uptake in the PD-L1 positive tumor.</p><h3>Conclusion</h3><p>Four biphenyl-based, ¹⁸F-labeled PD-L1 radioligands were developed using prosthetic groups (azido glycosyl or PEG2) for covalent fluorination and Al[¹⁸F]F²⁺-complexation with the RESCA chelator. Despite limited in vitro and in vivo performance, these fluorination approaches offer a foundation for developing improved PD-L1 radioligands after increasing the hydrophilicity and the spacing between the radiolabel and binding motif.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"10 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12214158/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144537579","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":"Protein-based Radiopharmaceuticals that target fibroblast activation protein alpha: a review of current progress","authors":"Abdelrahman Homedan,&nbsp;Darpan N. Pandya,&nbsp;Nicholas J. Schnicker,&nbsp;Thaddeus J. Wadas","doi":"10.1186/s41181-025-00356-5","DOIUrl":"10.1186/s41181-025-00356-5","url":null,"abstract":"<div><h3>Background</h3><p>Fibroblast activation protein alpha (FAP) is a serine protease that is expressed at basal levels in benign tissues but is overexpressed in a variety of pathologies, including cancer. Consequently, significant research efforts have been expended to develop diagnostic radiopharmaceuticals and effective radiotherapies that target this protein. The aim of this review is to summarize the current progress on the development of protein-based radiopharmaceuticals that target FAP.</p><h3>Main body</h3><p>A literature survey spanning nearly 40 years was conducted to assess the historical development and current progress in protein-based radiopharmaceuticals that target FAP. To date, more than 20 publications have been introduced that describe these agents in preclinical and clinical settings. This review summarizes the development and evaluation of radiopharmaceuticals involving antibodies, antibody fragments, and single domain antibodies.</p><h3>Conclusion</h3><p>The results of this literature review demonstrate that while significant research efforts have been expended on peptide-based radiopharmaceuticals and small molecule FAP inhibitors, the development of protein-based radiopharmaceuticals that target FAP remains an active research area that has yet to reach its full potential. </p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"10 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12182545/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144339704","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":"It’s a match: use of the radionuclide theranostic pair 133La/225Ac for the radiopharmacological characterization of EGFR-targeted single-domain antibodies","authors":"Johanna Trommer,&nbsp;Martin Ullrich,&nbsp;Falco Reissig,&nbsp;Santiago Andres Brühlmann,&nbsp;Anne-Kathrin Nitt-Weber,&nbsp;Zbynek Novy,&nbsp;Katarina Hajduova,&nbsp;Daniela Kurfurstova,&nbsp;Romana Hendrychova,&nbsp;Jan Bouchal,&nbsp;Milos Petrik,&nbsp;Christin Neuber,&nbsp;Wiebke Sihver,&nbsp;Sven Stadlbauer,&nbsp;Jens Pietzsch,&nbsp;Martin Kreller,&nbsp;Klaus Kopka,&nbsp;Constantin Mamat,&nbsp;Kristof Zarschler","doi":"10.1186/s41181-025-00354-7","DOIUrl":"10.1186/s41181-025-00354-7","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 &lt;span&gt;AbstractSection&lt;/span&gt;\u0000 Background\u0000 &lt;p&gt;Targeted alpha therapy represents an advanced and rapidly evolving form of precision cancer treatment with increasing importance in recent years. The alpha-emitter &lt;sup&gt;225&lt;/sup&gt;Ac plays a key role in this clinical development due to its attractive physical and chemical properties. In this context, the macropa chelator has favorable characteristics in terms of labeling conditions and complex stability, making its derivatives exceptionally appealing for &lt;sup&gt;225&lt;/sup&gt;Ac-labeling of heat-sensitive biomolecules. However, preclinical evaluation of such &lt;sup&gt;225&lt;/sup&gt;Ac-containing molecules and comprehensive assessment of their pharmacokinetics, dosimetry and radiobiology necessitate a suitable diagnostic counterpart. Due to its attractive radiation properties, &lt;sup&gt;133&lt;/sup&gt;La represents an adequate positron-emitting radionuclide to form a matched pair with &lt;sup&gt;225&lt;/sup&gt;Ac for macropa-based radiopharmaceuticals. Herein, we describe the preparation and radiopharmacological characterization of macropa-functionalized, &lt;sup&gt;133&lt;/sup&gt;La/&lt;sup&gt;225&lt;/sup&gt;Ac-labeled single-domain antibodies (sdAbs) targeting the epidermal growth factor receptor (EGFR) to demonstrate the general suitability of this theranostic pair of radionuclides.&lt;/p&gt;\u0000 \u0000 &lt;span&gt;AbstractSection&lt;/span&gt;\u0000 Results\u0000 &lt;p&gt;The synthesis of a clickable, bicyclononyne-modified macropa chelator and its site-specific conjugation to azide-modified, monovalent and biparatopic sdAbs is presented. Subsequent labeling at room temperature (rt) for 15 min resulted in molar activities of 30 MBq/nmol for &lt;sup&gt;133&lt;/sup&gt;La and 0.5 MBq/nmol for &lt;sup&gt;225&lt;/sup&gt;Ac, respectively. In vitro studies using the &lt;sup&gt;133&lt;/sup&gt;La-labeled sdAbs revealed comparable binding characteristics, but an enhanced cellular internalization of the biparatopic variant compared to its monovalent counterparts. This increased uptake consequently resulted in higher cytotoxicity of the &lt;sup&gt;225&lt;/sup&gt;Ac-labeled biparatopic conjugate. In vivo PET imaging of the &lt;sup&gt;133&lt;/sup&gt;La-labeled conjugates indicated comparable uptake and retention of the mono- and biparatopic variants in liver and kidneys, with the former showing slightly higher tumor accumulation. Ex vivo biodistribution studies conducted with &lt;sup&gt;225&lt;/sup&gt;Ac-labeled conjugates largely confirmed the findings obtained by PET imaging, albeit with a marginally higher tumor accumulation of the biparatopic &lt;sup&gt;225&lt;/sup&gt;Ac-radioimmunoconjugate. Final histological examinations of tumor and kidney tissues showed DNA damage in the renal cortex of the &lt;sup&gt;225&lt;/sup&gt;Ac-radioimmunoconjugate-treated mice, but no differences in the number of γ-H2AX-positive cells in the corresponding tumor tissues could be detected.&lt;/p&gt;\u0000 \u0000 &lt;span&gt;AbstractSection&lt;/span&gt;\u0000 Conclusions\u0000 &lt;p&gt;We present a comp","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"10 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12179020/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144324001","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}