Gu Jiwei, Zheng Ming-Qiang, Holden Daniel, Fowles Krista, Qiu Lin, Felchner Zachary, Zhang Li, Ropchan Jim, Gropler Robert J, Carson Richard E, Tu Zhude, Huang Yiyun, Hillmer Ansel T
Yale University.
Washington University School of Medicine in Saint Louis: Washington University in St Louis School of Medicine.
Res Sq. 2024 May 30:rs.3.rs-4350862. doi: 10.21203/rs.3.rs-4350862/v1.
The sphingosine-1-phosphate receptor-1 (S1PR) is involved in regulating responses to neuroimmune stimuli. There is a need for S1PR-specific radioligands with clinically suitable brain pharmcokinetic properties to complement existing radiotracers. This work evaluated a promising S1PR radiotracer, [F]TZ4877, in nonhuman primates.
[F]TZ4877 was produced via nucleophilic substitution of tosylate precursor with K[F]/F followed by deprotection. Brain PET imaging data were acquired with a Focus220 scanner in two (6, 13 years old) for 120-180 min following bolus injection of 118-163 MBq [F]TZ4877, with arterial blood sampling and metabolite analysis to measure the parent input function and plasma free fraction ( ). Each animal was scanned at baseline, 15-18 min after 0.047-0.063 mg/kg of the S1PR inhibitor ponesimod, 33 min after 0.4-0.8 mg/kg of the S1PR-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 ( / ). 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.
[F]TZ4877 exhibited fast kinetics that were described by the reversible 2-tissue compartment model. Baseline [F]TZ4877 was low (< 1%), and [F]TZ4877 / values were 233-866 mL/cm. TZ82112 dose-dependently reduced [F]TZ4877 / , while ponesimod and endotoxin exhibited negligible effects on / , 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.
[F]TZ4877 exhibits reversible kinetic properties, but the low value limits quantification with this radiotracer. S1PR is a compelling PET imaging target, and these data support pursuing alternative F-18 labeled radiotracers for potential future human studies.
1-磷酸鞘氨醇受体-1（S1PR）参与调节对神经免疫刺激的反应。需要具有临床适用脑药代动力学特性的S1PR特异性放射性配体来补充现有的放射性示踪剂。这项研究在非人灵长类动物中评估了一种有前景的S1PR放射性示踪剂[F]TZ4877。
[F]TZ4877通过用K[F]/F对甲苯磺酸酯前体进行亲核取代，然后脱保护来制备。在两只（6岁、13岁）动物中，在静脉推注118 - 163 MBq [F]TZ4877后的120 - 180分钟内，使用Focus220扫描仪采集脑PET成像数据，并进行动脉血采样和代谢物分析以测量母体输入函数和血浆游离分数（ ）。每只动物在基线、注射0.047 - 0.063 mg/kg的S1PR抑制剂波尼莫德后15 - 18分钟、注射0.4 - 0.8 mg/kg的S1PR特异性化合物TZ82112后33分钟以及注射1 ng/kg免疫刺激内毒素后167 - 195分钟进行扫描。使用代谢物校正输入函数进行动力学分析，以估计游离分数校正的总分布容积（ / ）。在2只动物（1只雄性，1只雌性）中使用Biograph Vision PET/CT系统进行全身剂量测定扫描，并使用OLINDA计算吸收辐射剂量估计值。
[F]TZ4877表现出快速动力学，可用可逆的双组织隔室模型描述。基线时[F]TZ4877 较低（< 1%），[F]TZ4877 / 值为233 - 866 mL/cm。TZ82112剂量依赖性地降低了[F]TZ4877 / ，而波尼莫德和内毒素对 / 的影响可忽略不计，这可能是由于扫描时间与给药时间的关系。剂量测定研究确定了麻醉的非人灵长类动物的关键器官为胆囊（雄性0.42、雌性0.31 mSv/MBq）。
[F]TZ4877表现出可逆的动力学特性，但低 值限制了使用该放射性示踪剂进行定量分析。S1PR是一个有吸引力的PET成像靶点，这些数据支持研发替代的F - 18标记放射性示踪剂，用于未来可能的人体研究。
