Herein we report an efficient radiolabeling of a 18 F-fluorinated derivative of dual inhibitor GW2580, with its subsequent evaluation as a positron emission tomography (PET) tracer candidate for imaging of two neuroreceptor targets implicated in the pathophysiology of neurodegeneration: tropomyosin receptor kinases (TrkB/C) and colony stimulating factor receptor (CSF-1R). [18 F]FOMPyD was synthesized from a boronic acid pinacolate precursor via copper-mediated 18 F-fluorination concerted with thermal deprotection of the four Boc groups on a diaminopyrimidine moiety in an 8.7±2.8% radiochemical yield, a radiochemical purity >99% and an effective molar activity of 187±93 GBq/μmol. [18 F]FOMPyD showed moderate brain permeability in wild-type rats (SUVmax = 0.75) and a slow washout rate. The brain uptake was partially reduced (ΔAUC40-90 = 11.6%) by administration of the non-radioactive FOMPyD (up to 30 μg/kg). In autoradiography, [18 F]FOMPyD exhibits ubiquitous distribution in rat and human brain tissues with relatively high non-specific binding revealed by self-blocking experiment. The binding was blocked by TrkB/C inhibitors, but not with a CSF-1R inhibitor, suggesting selective binding to the former receptor. Although an unfavorable pharmacokinetic profile will likely preclude application of [18 F]FOMPyD as a PET tracer for brain imaging, the concomitant one-pot copper-mediated 18 F-fluorination/Boc-deprotection is a practical technique for the automated radiosynthesis of acid-sensitive PET tracers.

中文翻译：

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[18 F]FOMPyD 作为 TrkB/C 受体成像 PET 示踪剂候选物的高效放射合成和临床前评估


在此，我们报告了双抑制剂 GW2580 的 18 F-氟化衍生物的有效放射性标记，随后将其评估为正电子发射断层扫描 (PET) 示踪剂候选物，用于对与神经变性病理生理学有关的两个神经受体靶标进行成像：原肌球蛋白受体激酶 (TrkB) /C) 和集落刺激因子受体 (CSF-1R)。 [ 18 F]FOMPyD是由硼酸频哪醇酯前体通过铜介导的18 F-氟化以及二氨基嘧啶部分上的四个Boc基团的热脱保护合成的，放射化学产率为8.7±2.8%，放射化学纯度为>99%，有效摩尔活性为187±93 GBq/μmol。 [18 F]FOMPyD 在野生型大鼠中表现出中等的脑通透性 (SUVmax = 0.75) 和缓慢的清除率。通过施用非放射性 FOMPyD（高达 30 μg/kg），大脑摄取部分减少（ΔAUC40-90 = 11.6%）。在放射自显影中，[18 F]FOMPyD 在大鼠和人脑组织中表现出普遍分布，并通过自阻断实验揭示了相对较高的非特异性结合。这种结合被 TrkB/C 抑制剂阻断，但不能被 CSF-1R 抑制剂阻断，这表明与前一种受体的选择性结合。尽管不利的药代动力学特征可能会妨碍 [18 F]FOMPyD 作为脑成像 PET 示踪剂的应用，但伴随的一锅铜介导的 18 F-氟化/Boc-去保护是一种用于自动放射合成酸-的实用技术。灵敏的 PET 示踪剂。