Designer Receptors Exclusively Activated by Designer Drugs (DREADD) are a preclinical chemogenetic approach with clinical potential for various disorders. In vivo visualization of DREADDs has been achieved with positron emission tomography (PET) using ¹¹C radiotracers. The objective of this study was to develop DREADD radiotracers labeled with ¹⁸F for a longer isotope half-life. A series of non-radioactive fluorinated analogs of clozapine with a wide range of in vitro binding affinities for the hM3Dq and hM4Di DREADD receptors has been synthesized for PET. Compound [¹⁸F]7b was radiolabeled via a modified ¹⁸F-deoxyfluorination protocol with a commercial ruthenium reagent. [¹⁸F]7b demonstrated encouraging PET imaging properties in a DREADD hM3Dq transgenic mouse model, whereas the radiotracer uptake in the wild type mouse brain was low. [¹⁸F]7b is a promising long-lived alternative to the DREADD radiotracers [¹¹C]clozapine ([¹¹C]CLZ) and [¹¹C]deschloroclozapine ([¹¹C]DCZ).

由设计药物独家激活的设计受体 (DREADD) 是一种临床前化学遗传学方法，具有治疗各种疾病的临床潜力。^使用11 C 放射性示踪剂通过正电子发射断层扫描 (PET) 实现了 DREADD 的体内可视化。本研究的目的是开发用¹⁸ F 标记的 DREADD 放射性示踪剂，以实现更长的同位素半衰期。已经为 PET 合成了一系列对 hM3Dq 和 hM4Di DREADD 受体具有广泛体外结合亲和力的氯氮平非放射性氟化类似物。化合物[ ¹⁸ F] 7b通过改进的¹⁸ F-脱氧氟化方案用商业钌试剂进行放射性标记。[ ¹⁸楼]图7b在 DREADD hM3Dq 转基因小鼠模型中展示了令人鼓舞的 PET 成像特性，而野生型小鼠大脑中的放射性示踪剂摄取量较低。[ ¹⁸ F] 7b是 DREADD 放射性示踪剂 [ ¹¹ C]clozapine ([ ¹¹ C]CLZ) 和 [ ¹¹ C]deschloroclozapine ([ ¹¹ C]DCZ) 的有前途的长寿命替代品。