ACS Pharmacology and Translational Science最新文献

{"title":"d4-Cystamine: A Deuterated Cystamine Derivative with Improved Anti-Inflammatory and Anti-Fibrotic Activities in a Murine Model of Fibrosing Steatohepatitis","authors":"Aleksandra Leszczynska,&nbsp;Thibault Alle,&nbsp;Benedikt Kaufmann,&nbsp;Hana Sung,&nbsp;Christian Stoess,&nbsp;Agustina Reca,&nbsp;Andrea Kim,&nbsp;Sun Kim,&nbsp;Chelsea Tran,&nbsp;Killian Oukoloff,&nbsp;Ludovica Monti,&nbsp;Bobby Lucero,&nbsp;Ilya Gertsman,&nbsp;Jeremiah D. Momper,&nbsp;Phillipp Hartmann,&nbsp;Ariel E. Feldstein*,&nbsp;Ranjan Dohil* and Carlo Ballatore*,&nbsp;","doi":"10.1021/acsptsci.4c0073810.1021/acsptsci.4c00738","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00738https://doi.org/10.1021/acsptsci.4c00738","url":null,"abstract":"<p >Metabolic dysfunction-associated steatotic liver disease (MASLD) is a multifactorial chronic disease that can progress to metabolic dysfunction-associated steatohepatitis (MASH) and liver fibrosis, ultimately leading to liver cirrhosis and hepatocellular carcinoma. Oxidative stress is believed to play an important role in the development of MASH. Small aminothiol compounds such as cysteamine and its oxidized precursor, cystamine, are known pleiotropic compounds that exhibit relatively potent antioxidant and other effects. Herein, we evaluate the efficacy of cystamine, as well as two deuterated derivatives, in a choline-deficient, L-amino acid-defined, high-fat-diet (CDAA-HFD) mouse model of rapidly progressing liver fibrosis. Compared to control mice, daily oral administration of isotopically reinforced cystamine derivatives (200 mg/kg) led to a significant reduction of liver fibrosis and inflammation as well as oxidative stress. Moreover, the efficacy of treatment appeared to increase with the deuteration state of cystamine, with the tetradeuterated derivative, <i>d</i>_<i>4</i>-cystamine, being the most effective. These results indicate that deuterated cystamine derivatives hold promise as potential candidates for the treatment of MASH.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 3","pages":"885–898 885–898"},"PeriodicalIF":4.9,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsptsci.4c00738","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143608889","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":"Single-Photon Emission Computer Tomography Imaging of Prostate-Specific Membrane Antigen (PSMA) Expression in Prostate Cancer Patients Using a Novel Peptide-Based Probe [99mTc]Tc-BQ0413 with Picomolar Affinity to PSMA: A Phase I/II Clinical Study","authors":"Anna Medvedeva,&nbsp;Vladimir Chernov,&nbsp;Maria Larkina,&nbsp;Anastasiya Rybina,&nbsp;Roman Zelchan,&nbsp;Olga Bragina,&nbsp;Ruslan Varvashenya,&nbsp;Olga Zebzeeva,&nbsp;Ekaterina Bezverkhniaia,&nbsp;Vladimir Tolmachev and Anna Orlova*,&nbsp;","doi":"10.1021/acsptsci.4c0063710.1021/acsptsci.4c00637","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00637https://doi.org/10.1021/acsptsci.4c00637","url":null,"abstract":"<p >Radionuclide imaging of prostate-specific membrane antigen (PSMA) expression can be used for staging prostate cancer. The pseudo-peptide [^99mTc]Tc-BQ0413 demonstrated high affinity and specificity to PSMA in preclinical evaluation. The purpose of this study was to clinically evaluate the safety and tolerability of a single administration of [^99mTc]Tc-BQ0413 as well as study its biodistribution using SPECT to estimate dosimetry. [^99mTc]Tc-BQ0413 was studied in a single-center diagnostic Phase I open-label exploratory study. Whole-body planar scintigraphy and SPECT/CT imaging were performed 2, 4, and 6 h after administration of 50, 100, or 150 μg (680 ± 140 MBq) of [^99mTc]Tc-BQ0413 in five PCa patients per injected mass (NCT05839990). All injections of [^99mTc]Tc-BQ0413 were well tolerated. The elimination of [^99mTc]Tc-BQ0413 was predominantly renal. The stable physiological uptake of [^99mTc]Tc-BQ0413 was observed in the lacrimal and salivary glands, liver, spleen, and kidneys for all tested peptide-injected masses. The average effective doses were 0.007 ± 0.001, 0.0049 ± 0.0003, and 0.0062 ± 0.0008 mSv/MBq for 50, 100, and 150 μg/injection, respectively. The radionuclide-associated dose burden per patient was 4–7 mSv/study for the given activity. Uptake of [^99mTc]Tc-BQ0413 in primary tumors was identified in all patients and increased with the peptide-injected mass. Uptake in lymph nodes and bone metastases was the highest at 100 μg/injected mass. The highest tumor lesion/background ratios were observed 6 h after the administration of 100 μg of [^99mTc]Tc-BQ0413. The results of the Phase I study showed that injections of [^99mTc]Tc-BQ0413 were well tolerated, safe, and associated with low absorbed doses. Imaging using [^99mTc]Tc-BQ0413 enabled the visualization of primary prostate cancer lesions as well as metastases in lymph nodes and bones.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 3","pages":"736–747 736–747"},"PeriodicalIF":4.9,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsptsci.4c00637","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143608846","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":"<i>Immuno-</i>μSARS2 Chip: A Peptide-Based Microarray to Assess COVID-19 Prognosis Based on Immunological Fingerprints.","authors":"Julian Guercetti, Marc Alorda, Luciano Sappia, Roger Galve, Macarena Duran-Corbera, Daniel Pulido, Ginevra Berardi, Miriam Royo, Alicia Lacoma, José Muñoz, Eduardo Padilla, Silvia Castañeda, Elena Sendra, Juan P Horcajada, Agustín Gutierrez-Galvez, Santiago Marco, J-Pablo Salvador, M-Pilar Marco","doi":"10.1021/acsptsci.4c00727","DOIUrl":"10.1021/acsptsci.4c00727","url":null,"abstract":"<p><p>A multiplexed microarray chip (<i>Immuno</i>-μSARS2) aiming at providing information on the prognosis of the COVID-19 has been developed. The diagnostic technology records information related to the profile of the immunological response of patients infected by the SARS-CoV-2 virus. The diagnostic technology delivers information on the avidity of the sera against 28 different peptide epitopes and 7 proteins printed on a 25 mm² area of a glass slide. The peptide epitopes (12-15 mer) derived from structural proteins (Spike and Nucleocapsid) have been rationally designed, synthesized, and used to develop <i>Immuno</i>-μSARS2 as a multiplexed and high-throughput fluorescent microarray platform. The analysis of 755 human serum samples (321 from PCR+ patients; 288 from PCR- patients; 115 from prepandemic individuals and classified as hospitalized, admitted to intensive-care unit (ICU), and <i>exitus</i>) from three independent cohorts has shown that the chips perform with a 98% specificity and 91% sensitivity identifying RT-PCR+ patients. Computational analysis utilized to correlate the immunological signatures of the samples analyzed indicate significant prediction rates against <i>exitus</i> conditions with 82% accuracy, ICU admissions with 80% accuracy, and 73% accuracy over hospitalization requirement compared to asymptomatic patients' fingerprints. The miniaturized microarray chip allows simultaneous determination of 96 samples (24 samples/slide) in 90 min and requires only 10 μL of sera. The diagnostic approach presented for the first time here could have a great value in assisting clinicians in decision-making based on the information provided by the <i>Immuno</i>-μSARS2 regarding progression of the disease and could be easily implemented in diagnostics of other infectious diseases.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 3","pages":"871-884"},"PeriodicalIF":4.9,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11915183/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143664878","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":"Immuno-μSARS2 Chip: A Peptide-Based Microarray to Assess COVID-19 Prognosis Based on Immunological Fingerprints","authors":"Julian Guercetti,&nbsp;Marc Alorda,&nbsp;Luciano Sappia,&nbsp;Roger Galve,&nbsp;Macarena Duran-Corbera,&nbsp;Daniel Pulido,&nbsp;Ginevra Berardi,&nbsp;Miriam Royo,&nbsp;Alicia Lacoma,&nbsp;José Muñoz,&nbsp;Eduardo Padilla,&nbsp;Silvia Castañeda,&nbsp;Elena Sendra,&nbsp;Juan P. Horcajada,&nbsp;Agustín Gutierrez-Galvez,&nbsp;Santiago Marco,&nbsp;J.-Pablo Salvador* and M.-Pilar Marco,&nbsp;","doi":"10.1021/acsptsci.4c0072710.1021/acsptsci.4c00727","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00727https://doi.org/10.1021/acsptsci.4c00727","url":null,"abstract":"<p >A multiplexed microarray chip (<i>Immuno</i>-μSARS2) aiming at providing information on the prognosis of the COVID-19 has been developed. The diagnostic technology records information related to the profile of the immunological response of patients infected by the SARS-CoV-2 virus. The diagnostic technology delivers information on the avidity of the sera against 28 different peptide epitopes and 7 proteins printed on a 25 mm² area of a glass slide. The peptide epitopes (12–15 mer) derived from structural proteins (Spike and Nucleocapsid) have been rationally designed, synthesized, and used to develop <i>Immuno</i>-μSARS2 as a multiplexed and high-throughput fluorescent microarray platform. The analysis of 755 human serum samples (321 from PCR+ patients; 288 from PCR– patients; 115 from prepandemic individuals and classified as hospitalized, admitted to intensive-care unit (ICU), and <i>exitus</i>) from three independent cohorts has shown that the chips perform with a 98% specificity and 91% sensitivity identifying RT-PCR+ patients. Computational analysis utilized to correlate the immunological signatures of the samples analyzed indicate significant prediction rates against <i>exitus</i> conditions with 82% accuracy, ICU admissions with 80% accuracy, and 73% accuracy over hospitalization requirement compared to asymptomatic patients’ fingerprints. The miniaturized microarray chip allows simultaneous determination of 96 samples (24 samples/slide) in 90 min and requires only 10 μL of sera. The diagnostic approach presented for the first time here could have a great value in assisting clinicians in decision-making based on the information provided by the <i>Immuno</i>-μSARS2 regarding progression of the disease and could be easily implemented in diagnostics of other infectious diseases.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 3","pages":"871–884 871–884"},"PeriodicalIF":4.9,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsptsci.4c00727","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143608796","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":"Single-Photon Emission Computer Tomography Imaging of Prostate-Specific Membrane Antigen (PSMA) Expression in Prostate Cancer Patients Using a Novel Peptide-Based Probe [^99mTc]Tc-BQ0413 with Picomolar Affinity to PSMA: A Phase I/II Clinical Study.","authors":"Anna Medvedeva, Vladimir Chernov, Maria Larkina, Anastasiya Rybina, Roman Zelchan, Olga Bragina, Ruslan Varvashenya, Olga Zebzeeva, Ekaterina Bezverkhniaia, Vladimir Tolmachev, Anna Orlova","doi":"10.1021/acsptsci.4c00637","DOIUrl":"10.1021/acsptsci.4c00637","url":null,"abstract":"<p><p>Radionuclide imaging of prostate-specific membrane antigen (PSMA) expression can be used for staging prostate cancer. The pseudo-peptide [^99mTc]Tc-BQ0413 demonstrated high affinity and specificity to PSMA in preclinical evaluation. The purpose of this study was to clinically evaluate the safety and tolerability of a single administration of [^99mTc]Tc-BQ0413 as well as study its biodistribution using SPECT to estimate dosimetry. [^99mTc]Tc-BQ0413 was studied in a single-center diagnostic Phase I open-label exploratory study. Whole-body planar scintigraphy and SPECT/CT imaging were performed 2, 4, and 6 h after administration of 50, 100, or 150 μg (680 ± 140 MBq) of [^99mTc]Tc-BQ0413 in five PCa patients per injected mass (NCT05839990). All injections of [^99mTc]Tc-BQ0413 were well tolerated. The elimination of [^99mTc]Tc-BQ0413 was predominantly renal. The stable physiological uptake of [^99mTc]Tc-BQ0413 was observed in the lacrimal and salivary glands, liver, spleen, and kidneys for all tested peptide-injected masses. The average effective doses were 0.007 ± 0.001, 0.0049 ± 0.0003, and 0.0062 ± 0.0008 mSv/MBq for 50, 100, and 150 μg/injection, respectively. The radionuclide-associated dose burden per patient was 4-7 mSv/study for the given activity. Uptake of [^99mTc]Tc-BQ0413 in primary tumors was identified in all patients and increased with the peptide-injected mass. Uptake in lymph nodes and bone metastases was the highest at 100 μg/injected mass. The highest tumor lesion/background ratios were observed 6 h after the administration of 100 μg of [^99mTc]Tc-BQ0413. The results of the Phase I study showed that injections of [^99mTc]Tc-BQ0413 were well tolerated, safe, and associated with low absorbed doses. Imaging using [^99mTc]Tc-BQ0413 enabled the visualization of primary prostate cancer lesions as well as metastases in lymph nodes and bones.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 3","pages":"736-747"},"PeriodicalIF":4.9,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11915028/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143665079","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":"Comparative Evaluation and Profiling of Chemical Tools for the Nuclear Hormone Receptor Family 2","authors":"Max Lewandowski,&nbsp;Romy Busch,&nbsp;Julian A. Marschner and Daniel Merk*,&nbsp;","doi":"10.1021/acsptsci.4c0071910.1021/acsptsci.4c00719","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00719https://doi.org/10.1021/acsptsci.4c00719","url":null,"abstract":"<p >Nuclear receptors regulate transcription in response to ligand signals and enable the pharmacological control of gene expression. However, many nuclear receptors are still poorly explored and are not accessible to ligand-based target identification studies. In particular, most members of the NR2 family are among the least studied proteins of the class, and apart from the retinoid X receptors (RXR), validated NR2 ligands are very rare. Here, we gathered the NR2 modulators reported in the literature for comparative profiling in uniform test systems. Most candidate compounds displayed insufficient on-target activity or selectivity to be used as chemical tools for NR2 receptors, underscoring the urgent need for further NR2 ligand development. Nevertheless, a small NR2 modulator set could be assembled for application in a chemogenomic fashion.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 3","pages":"854–870 854–870"},"PeriodicalIF":4.9,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143608793","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In Situ Mass Spectrometry Imaging to Elucidate the Effects of an Adenosine A2A Receptor Agonist and Alprazolam on Sleep Regulation","authors":"Yi Zhang,&nbsp;Guixiang Yang,&nbsp;Qian Jin,&nbsp;Tong Shi,&nbsp;Xuejun Chen,&nbsp;Ruihua Zhang,&nbsp;Chen Wang* and Liqin Li*,&nbsp;","doi":"10.1021/acsptsci.4c0070710.1021/acsptsci.4c00707","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00707https://doi.org/10.1021/acsptsci.4c00707","url":null,"abstract":"<p >Alprazolam (Alp), a commonly used sleep medication in clinical practice, has several potential limitations, including a narrow therapeutic dosage range and a delayed sleep onset. CGS21680 (CGS), a selective agonist of the adenosine A_2A receptor, exhibits neuroinhibitory properties. This study aimed to evaluate the effects of CGS on the sleep properties of Alp. The sleep-inducing effects of Alp were assessed through the righting reflex, while the sedative effects of CGS were evaluated by spontaneous activity detection. The synergistic effect of CGS on Alp was evaluated by using electroencephalography and electromyography. The results indicate that we optimized and selected ED₅ dose of Alp and ED₅₀ dose of CGS for coadministration. CGS reduced the sleep latency induced by Alp and extended the sleep duration. The distribution of Alp in the brain was assessed through mass spectrometry imaging (MSI). The blood–brain barrier (BBB) model was established to evaluate the impact of CGS on the transmittance of Alp. The results indicated that CGS influenced the distribution of Alp across various brain regions and increased Alp’s transmittance across the BBB. The metabolic pathways of GABA, glutamate, and glutamine were assessed through MSI and enzyme activity verification. The coadministration of Alp and CGS resulted in the regulation of GABA, glutamate, and glutamine during the sleep latency and sleep maintenance periods, respectively. In conclusion, the potentiating effect of CGS on the sleep-inducing properties of Alp is attributed to its ability to modulate the distribution of Alp in the brain by enhancing BBB permeability and its influence on Alp-induced neurotransmitter release.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 3","pages":"841–853 841–853"},"PeriodicalIF":4.9,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143609110","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In Situ Mass Spectrometry Imaging to Elucidate the Effects of an Adenosine A_2A Receptor Agonist and Alprazolam on Sleep Regulation.","authors":"Yi Zhang, Guixiang Yang, Qian Jin, Tong Shi, Xuejun Chen, Ruihua Zhang, Chen Wang, Liqin Li","doi":"10.1021/acsptsci.4c00707","DOIUrl":"10.1021/acsptsci.4c00707","url":null,"abstract":"<p><p>Alprazolam (Alp), a commonly used sleep medication in clinical practice, has several potential limitations, including a narrow therapeutic dosage range and a delayed sleep onset. CGS21680 (CGS), a selective agonist of the adenosine A_2A receptor, exhibits neuroinhibitory properties. This study aimed to evaluate the effects of CGS on the sleep properties of Alp. The sleep-inducing effects of Alp were assessed through the righting reflex, while the sedative effects of CGS were evaluated by spontaneous activity detection. The synergistic effect of CGS on Alp was evaluated by using electroencephalography and electromyography. The results indicate that we optimized and selected ED₅ dose of Alp and ED₅₀ dose of CGS for coadministration. CGS reduced the sleep latency induced by Alp and extended the sleep duration. The distribution of Alp in the brain was assessed through mass spectrometry imaging (MSI). The blood-brain barrier (BBB) model was established to evaluate the impact of CGS on the transmittance of Alp. The results indicated that CGS influenced the distribution of Alp across various brain regions and increased Alp's transmittance across the BBB. The metabolic pathways of GABA, glutamate, and glutamine were assessed through MSI and enzyme activity verification. The coadministration of Alp and CGS resulted in the regulation of GABA, glutamate, and glutamine during the sleep latency and sleep maintenance periods, respectively. In conclusion, the potentiating effect of CGS on the sleep-inducing properties of Alp is attributed to its ability to modulate the distribution of Alp in the brain by enhancing BBB permeability and its influence on Alp-induced neurotransmitter release.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 3","pages":"841-853"},"PeriodicalIF":4.9,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11915180/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143664922","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":"Impact of Radiometal Chelates on In Vivo Visualization of Immune Checkpoint Protein Using Radiolabeled Affibody Molecules","authors":"Vladimir Tolmachev,&nbsp;Eleftherios Papalanis,&nbsp;Ekaterina A. Bezverkhniaia,&nbsp;Alia Hani Rosly,&nbsp;Anzhelika Vorobyeva,&nbsp;Anna Orlova,&nbsp;Matilda Carlqvist,&nbsp;Fredrik Y. Frejd and Maryam Oroujeni*,&nbsp;","doi":"10.1021/acsptsci.4c0053910.1021/acsptsci.4c00539","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00539https://doi.org/10.1021/acsptsci.4c00539","url":null,"abstract":"<p >The immune checkpoint protein B7–H3 (CD276) is overexpressed in various cancers and is an attractive target for the treatment of malignant tumors. Radionuclide molecular imaging of B7–H3 expression using engineered scaffold proteins such as Affibody molecules is a promising strategy for the selection of potential responders to B7–H3-targeted therapy. Feasibility of B7–H3 imaging was demonstrated using two ^99mTc-labeled probes, AC12 and an affinity-matured SYNT179 using a [^99mTc]Tc-GGGC label. This study aimed to evaluate whether the use of a residualizing ¹¹¹In-based label provides better imaging contrast compared with a nonresidualizing label. To do that, SYNT179 and AC12-GGGC Affibody molecules were labeled with ¹¹¹In using (4,10-bis-carboxymethyl-7-{[2-(2,5-dioxo-3-thioxo-pyrrolidin-1-yl)-ethylcarbamoyl]-methyl}-1,4,7,10-tetraaza-cyclododec-1-yl)-acetic acid (maleimide-DOTA) chelator, site-specifically coupled to the C-terminus of Affibody molecules. The binding affinities of the ¹¹¹In-labeled conjugates to B7–H3-expressing living cells were higher compared with the affinities of the ^99mTc-labeled variants. In mice with B7–H3-expressing xenografts, the tumor uptake of ¹¹¹In-labeled proteins (3.6 ± 0.3 and 1.8 ± 0.5%ID/g for [¹¹¹In]In-SYNT179-DOTA and [¹¹¹In]In-AC12-DOTA, respectively) was significantly (<i>p</i> &lt; 0.05, ANOVA) higher than those for ^99mTc-labeled counterparts (1.6 ± 0.2%ID/g and 0.8 ± 0.2%ID/g for [^99mTc]Tc-SYNT179 and [^99mTc]Tc-AC12-GGGC, respectively). The best variant, [¹¹¹In]In-SYNT179-DOTA, provided a tumor-to-blood ratio of 31.1 ± 2.9, which was twice higher than that for [^99mTc]Tc-SYNT179 and 7-fold higher than that for [^99mTc]Tc-AC12-GGGC. Both ¹¹¹In-labeled Affibody molecules had higher renal retention compared with ^99mTc-labeled ones, but the hepatobiliary excretion of ¹¹¹In-labeled proteins was appreciably lower, potentially improving the imaging of abdominal metastases. Overall, [¹¹¹In]In-SYNT179-DOTA is the most promising tracer for visualization of B7–H3 expression.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 3","pages":"706–717 706–717"},"PeriodicalIF":4.9,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsptsci.4c00539","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143609107","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":"Impact of Radiometal Chelates on In Vivo Visualization of Immune Checkpoint Protein Using Radiolabeled Affibody Molecules.","authors":"Vladimir Tolmachev, Eleftherios Papalanis, Ekaterina A Bezverkhniaia, Alia Hani Rosly, Anzhelika Vorobyeva, Anna Orlova, Matilda Carlqvist, Fredrik Y Frejd, Maryam Oroujeni","doi":"10.1021/acsptsci.4c00539","DOIUrl":"10.1021/acsptsci.4c00539","url":null,"abstract":"<p><p>The immune checkpoint protein B7-H3 (CD276) is overexpressed in various cancers and is an attractive target for the treatment of malignant tumors. Radionuclide molecular imaging of B7-H3 expression using engineered scaffold proteins such as Affibody molecules is a promising strategy for the selection of potential responders to B7-H3-targeted therapy. Feasibility of B7-H3 imaging was demonstrated using two ^99mTc-labeled probes, AC12 and an affinity-matured SYNT179 using a [^99mTc]Tc-GGGC label. This study aimed to evaluate whether the use of a residualizing ¹¹¹In-based label provides better imaging contrast compared with a nonresidualizing label. To do that, SYNT179 and AC12-GGGC Affibody molecules were labeled with ¹¹¹In using (4,10-bis-carboxymethyl-7-{[2-(2,5-dioxo-3-thioxo-pyrrolidin-1-yl)-ethylcarbamoyl]-methyl}-1,4,7,10-tetraaza-cyclododec-1-yl)-acetic acid (maleimide-DOTA) chelator, site-specifically coupled to the C-terminus of Affibody molecules. The binding affinities of the ¹¹¹In-labeled conjugates to B7-H3-expressing living cells were higher compared with the affinities of the ^99mTc-labeled variants. In mice with B7-H3-expressing xenografts, the tumor uptake of ¹¹¹In-labeled proteins (3.6 ± 0.3 and 1.8 ± 0.5%ID/g for [¹¹¹In]In-SYNT179-DOTA and [¹¹¹In]In-AC12-DOTA, respectively) was significantly (<i>p</i> < 0.05, ANOVA) higher than those for ^99mTc-labeled counterparts (1.6 ± 0.2%ID/g and 0.8 ± 0.2%ID/g for [^99mTc]Tc-SYNT179 and [^99mTc]Tc-AC12-GGGC, respectively). The best variant, [¹¹¹In]In-SYNT179-DOTA, provided a tumor-to-blood ratio of 31.1 ± 2.9, which was twice higher than that for [^99mTc]Tc-SYNT179 and 7-fold higher than that for [^99mTc]Tc-AC12-GGGC. Both ¹¹¹In-labeled Affibody molecules had higher renal retention compared with ^99mTc-labeled ones, but the hepatobiliary excretion of ¹¹¹In-labeled proteins was appreciably lower, potentially improving the imaging of abdominal metastases. Overall, [¹¹¹In]In-SYNT179-DOTA is the most promising tracer for visualization of B7-H3 expression.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 3","pages":"706-717"},"PeriodicalIF":4.9,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11915182/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143664919","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}