非人灵长类动物鞘氨醇-1-磷酸受体1 [18F]TZ4877的PET成像

IF 3 4区医学 Q2 RADIOLOGY, NUCLEAR MEDICINE & MEDICAL IMAGING

Molecular Imaging and Biology Pub Date : 2025-02-01 Epub Date: 2025-01-08 DOI:10.1007/s11307-024-01979-x

Jiwei Gu, Ming-Qiang Zheng, Daniel Holden, Krista Fowles, Lin Qiu, Zachary Felchner, Li Zhang, Jim Ropchan, Robert J Gropler, Richard E Carson, Zhude Tu, Yiyun Huang, Ansel T Hillmer

{"title":"非人灵长类动物鞘氨醇-1-磷酸受体1 [18F]TZ4877的PET成像","authors":"Jiwei Gu, Ming-Qiang Zheng, Daniel Holden, Krista Fowles, Lin Qiu, Zachary Felchner, Li Zhang, Jim Ropchan, Robert J Gropler, Richard E Carson, Zhude Tu, Yiyun Huang, Ansel T Hillmer","doi":"10.1007/s11307-024-01979-x","DOIUrl":null,"url":null,"abstract":"Purpose: The sphingosine-1-phosphate receptor-1 (S1PR1) is involved in regulating responses to neuroimmune stimuli. There is a need for S1PR1-specific radioligands with clinically suitable brain pharmcokinetic properties to complement existing radiotracers. This work evaluated a promising S1PR1 radiotracer, [18F]TZ4877, in nonhuman primates.Procedures: [18F]TZ4877 was produced via nucleophilic substitution of tosylate precursor with K[18F]/F- followed by deprotection. Brain PET imaging data were acquired with a Focus220 scanner in two Macaca mulatta (6, 13 years old) for 120-180 min following bolus injection of 118-163 MBq [18F]TZ4877, with arterial blood sampling and metabolite analysis to measure the parent input function and plasma free fraction (fP). Each animal was scanned at baseline, 15-18 min after 0.047-0.063 mg/kg of the S1PR1 inhibitor ponesimod, 33 min after 0.4-0.8 mg/kg of the S1PR1-specific compound TZ82112, and 167-195 min after 1 ng/kg of the immune stimulus endotoxin. Kinetic analysis with metabolite-corrected input function was performed to estimate the free fraction corrected total distribution volume (VT/fP). Whole-body dosimetry scans were acquired in 2 animals (1M, 1F) with a Biograph Vision PET/CT System, and absorbed radiation dose estimates were calculated with OLINDA.Results: [18F]TZ4877 exhibited fast kinetics that were described by the reversible 2-tissue compartment model. Baseline [18F]TZ4877 fP was low (<1%), and [18F]TZ4877 VT/fP values were 233-866 mL/cm3. TZ82112 dose-dependently reduced [18F]TZ4877 VT/fP, while ponesimod and endotoxin exhibited negligible effects on VT/fP, possibly due to scan timing relative to dosing. Dosimetry studies identified the critical organs of gallbladder (0.42 (M) and 0.31 (F) mSv/MBq) for anesthetized nonhuman primate.Conclusions: [18F]TZ4877 exhibits reversible kinetic properties, but the low fP value limits reproducible quantification with this radiotracer. S1PR1 is a compelling PET imaging target, and these data support pursuing alternative F-18 labeled radiotracers for potential future human studies.","PeriodicalId":18760,"journal":{"name":"Molecular Imaging and Biology","volume":" ","pages":"54-63"},"PeriodicalIF":3.0000,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"PET Imaging of Sphingosine-1-Phosphate Receptor 1 with [18F]TZ4877 in Nonhuman Primates.\",\"authors\":\"Jiwei Gu, Ming-Qiang Zheng, Daniel Holden, Krista Fowles, Lin Qiu, Zachary Felchner, Li Zhang, Jim Ropchan, Robert J Gropler, Richard E Carson, Zhude Tu, Yiyun Huang, Ansel T Hillmer\",\"doi\":\"10.1007/s11307-024-01979-x\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Purpose: The sphingosine-1-phosphate receptor-1 (S1PR1) is involved in regulating responses to neuroimmune stimuli. There is a need for S1PR1-specific radioligands with clinically suitable brain pharmcokinetic properties to complement existing radiotracers. This work evaluated a promising S1PR1 radiotracer, [18F]TZ4877, in nonhuman primates.Procedures: [18F]TZ4877 was produced via nucleophilic substitution of tosylate precursor with K[18F]/F- followed by deprotection. Brain PET imaging data were acquired with a Focus220 scanner in two Macaca mulatta (6, 13 years old) for 120-180 min following bolus injection of 118-163 MBq [18F]TZ4877, with arterial blood sampling and metabolite analysis to measure the parent input function and plasma free fraction (fP). Each animal was scanned at baseline, 15-18 min after 0.047-0.063 mg/kg of the S1PR1 inhibitor ponesimod, 33 min after 0.4-0.8 mg/kg of the S1PR1-specific compound TZ82112, and 167-195 min after 1 ng/kg of the immune stimulus endotoxin. Kinetic analysis with metabolite-corrected input function was performed to estimate the free fraction corrected total distribution volume (VT/fP). Whole-body dosimetry scans were acquired in 2 animals (1M, 1F) with a Biograph Vision PET/CT System, and absorbed radiation dose estimates were calculated with OLINDA.Results: [18F]TZ4877 exhibited fast kinetics that were described by the reversible 2-tissue compartment model. Baseline [18F]TZ4877 fP was low (<1%), and [18F]TZ4877 VT/fP values were 233-866 mL/cm3. TZ82112 dose-dependently reduced [18F]TZ4877 VT/fP, while ponesimod and endotoxin exhibited negligible effects on VT/fP, possibly due to scan timing relative to dosing. Dosimetry studies identified the critical organs of gallbladder (0.42 (M) and 0.31 (F) mSv/MBq) for anesthetized nonhuman primate.Conclusions: [18F]TZ4877 exhibits reversible kinetic properties, but the low fP value limits reproducible quantification with this radiotracer. S1PR1 is a compelling PET imaging target, and these data support pursuing alternative F-18 labeled radiotracers for potential future human studies.\",\"PeriodicalId\":18760,\"journal\":{\"name\":\"Molecular Imaging and Biology\",\"volume\":\" \",\"pages\":\"54-63\"},\"PeriodicalIF\":3.0000,\"publicationDate\":\"2025-02-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Molecular Imaging and Biology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1007/s11307-024-01979-x\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/1/8 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q2\",\"JCRName\":\"RADIOLOGY, NUCLEAR MEDICINE & MEDICAL IMAGING\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Imaging and Biology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s11307-024-01979-x","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/1/8 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"RADIOLOGY, NUCLEAR MEDICINE & MEDICAL IMAGING","Score":null,"Total":0}

引用次数: 0

摘要

目的：鞘氨醇-1-磷酸受体1 （S1PR1）参与调节对神经免疫刺激的反应。需要具有临床合适的脑药代动力学特性的s1pr1特异性放射性配体来补充现有的放射性示踪剂。这项工作评估了一种有前途的S1PR1放射性示踪剂[18F]TZ4877在非人灵长类动物中的应用。步骤：[18F]TZ4877通过K[18F]/F-亲核取代tosylate前体，然后脱保护。两只猕猴（6,13岁）在注射118-163 MBq [18F]TZ4877后，用Focus220扫描仪获得120-180分钟的脑PET成像数据，并进行动脉采血和代谢物分析，测量亲本输入功能和血浆游离分数（fP）。每只动物在基线、0.047-0.063 mg/kg的S1PR1抑制剂ponesimod后15-18分钟、0.4-0.8 mg/kg的S1PR1特异性化合物TZ82112后33分钟、1 ng/kg的免疫刺激内毒素后167-195分钟进行扫描。采用代谢校正输入函数进行动力学分析，估计游离分数校正总分布体积（VT/fP）。使用Biograph Vision PET/CT系统对2只动物（1M, 1F）进行全身剂量学扫描，并使用OLINDA计算吸收辐射剂量估计。结果：[18F]TZ4877表现出快速动力学，可由可逆的2组织室模型描述。基线[18F]TZ4877 fP较低(18F]TZ4877 VT/fP值为233-866 mL/cm3。TZ82112剂量依赖性地降低了[18F]TZ4877 VT/fP，而ponesimod和内毒素对VT/fP的影响可以忽略不计，可能是由于扫描时间与剂量相关。剂量学研究确定了麻醉的非人灵长类动物的关键器官胆囊(0.42 （M)和0.31 (F) mSv/MBq）。结论：[18F]TZ4877表现出可逆的动力学性质，但低fP值限制了该放射性示踪剂的可重复性定量。S1PR1是一个引人注目的PET成像目标，这些数据支持寻求替代F-18标记的放射性示踪剂，用于潜在的未来人类研究。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

查看原文本刊更多论文

PET Imaging of Sphingosine-1-Phosphate Receptor 1 with [¹⁸F]TZ4877 in Nonhuman Primates.

Purpose: The sphingosine-1-phosphate receptor-1 (S1PR₁) is involved in regulating responses to neuroimmune stimuli. There is a need for S1PR₁-specific radioligands with clinically suitable brain pharmcokinetic properties to complement existing radiotracers. This work evaluated a promising S1PR₁ radiotracer, [¹⁸F]TZ4877, in nonhuman primates.

Procedures: [¹⁸F]TZ4877 was produced via nucleophilic substitution of tosylate precursor with K[¹⁸F]/F^- followed by deprotection. Brain PET imaging data were acquired with a Focus220 scanner in two Macaca mulatta (6, 13 years old) for 120-180 min following bolus injection of 118-163 MBq [¹⁸F]TZ4877, with arterial blood sampling and metabolite analysis to measure the parent input function and plasma free fraction (f_P). Each animal was scanned at baseline, 15-18 min after 0.047-0.063 mg/kg of the S1PR₁ inhibitor ponesimod, 33 min after 0.4-0.8 mg/kg of the S1PR₁-specific compound TZ82112, and 167-195 min after 1 ng/kg of the immune stimulus endotoxin. Kinetic analysis with metabolite-corrected input function was performed to estimate the free fraction corrected total distribution volume (V_T/f_P). Whole-body dosimetry scans were acquired in 2 animals (1M, 1F) with a Biograph Vision PET/CT System, and absorbed radiation dose estimates were calculated with OLINDA.

Results: [¹⁸F]TZ4877 exhibited fast kinetics that were described by the reversible 2-tissue compartment model. Baseline [¹⁸F]TZ4877 f_P was low (<1%), and [¹⁸F]TZ4877 V_T/f_P values were 233-866 mL/cm³. TZ82112 dose-dependently reduced [¹⁸F]TZ4877 V_T/f_P, while ponesimod and endotoxin exhibited negligible effects on V_T/f_P, possibly due to scan timing relative to dosing. Dosimetry studies identified the critical organs of gallbladder (0.42 (M) and 0.31 (F) mSv/MBq) for anesthetized nonhuman primate.

Conclusions: [¹⁸F]TZ4877 exhibits reversible kinetic properties, but the low f_P value limits reproducible quantification with this radiotracer. S1PR₁ is a compelling PET imaging target, and these data support pursuing alternative F-18 labeled radiotracers for potential future human studies.

求助全文

通过发布文献求助，成功后即可免费获取论文全文。去求助

来源期刊

Molecular Imaging and Biology 医学-核医学

CiteScore

6.90

自引率

3.20%

发文量

审稿时长

3 months

期刊介绍： Molecular Imaging and Biology (MIB) invites original contributions (research articles, review articles, commentaries, etc.) on the utilization of molecular imaging (i.e., nuclear imaging, optical imaging, autoradiography and pathology, MRI, MPI, ultrasound imaging, radiomics/genomics etc.) to investigate questions related to biology and health. The objective of MIB is to provide a forum to the discovery of molecular mechanisms of disease through the use of imaging techniques. We aim to investigate the biological nature of disease in patients and establish new molecular imaging diagnostic and therapy procedures. Some areas that are covered are: Preclinical and clinical imaging of macromolecular targets (e.g., genes, receptors, enzymes) involved in significant biological processes. The design, characterization, and study of new molecular imaging probes and contrast agents for the functional interrogation of macromolecular targets. Development and evaluation of imaging systems including instrumentation, image reconstruction algorithms, image analysis, and display. Development of molecular assay approaches leading to quantification of the biological information obtained in molecular imaging. Study of in vivo animal models of disease for the development of new molecular diagnostics and therapeutics. Extension of in vitro and in vivo discoveries using disease models, into well designed clinical research investigations. Clinical molecular imaging involving clinical investigations, clinical trials and medical management or cost-effectiveness studies.