Serotonin 1A (5-HT1A) receptors are implicated in the pathogenesis of several psychiatric and neurodegenerative disorders motivating the development of suitable radiotracers for in vivo positron emission tomography (PET) neuroimaging. The gold standard PET imaging agent for this target is [carbonyl-11C]WAY-100635, labeled via a technically challenging multi-step reaction that has limited its widespread use. While several antagonist and agonist-based PET radiotracers for 5-HT 1A receptors have been developed, their clinical translation has been hindered by methodological challenges and/or and non-specific binding. As a result, there is continued interest in the development of new and more selective 5-HT1A PET tracers having a relatively easier and reliable radiosynthesis process for routine production and with favorable metabolism to facilitate tracer-kinetic modeling. The purpose of the current study was to develop and characterize a radioligand with suitable characteristics for imaging 5-HT1A receptors in the brain. The current study reports the in vitro characterization and radiosyntheses of three candidate 5-HT1A receptor antagonists, DF-100 (1), DF-300 (2) and DF-400 (3), to explore their suitability as potential PET radiotracers. Syntheses of 1–3 and corresponding precursors for radiolabeling were achieved from isonicotinic, picolinic acid or picolino nitrile. In vitro binding studies demonstrated nanomolar affinity of the compounds for 5-HT1A receptors. Binding of 1–3 for other biogenic amines, neurotransmitter receptors, and transporters was negligible with the exception of moderate affinities for α1-adrenergic receptors (4–6-fold less potent than that for 5-HT1A receptor). Radioligands [11C]1–3 were efficiently prepared by 11C-O-methylation of the corresponding phenolic precursor in non-decay corrected radiochemical yields of 7–11% with > 99% chemical and radiochemical purities. Dynamic PET studies in rats demonstrated negligible brain uptake of [11C]1 and [11C]2. In contrast, significant brain uptake of [11C]3 was observed with an early peak SUV of 4–5. However, [11C]3 displayed significant off-target binding attributed to α1-adrenergic receptors based on regional distribution (thalamus>hippocampus) and blocking studies. Despite efficient radiolabeling, results from PET imaging experiments limit the application of [11C]3 for in vivo quantification of 5-HT1A receptors. Nevertheless, derivatives of compound 3 may provide a scaffold for alternative PET radiotracers with improved selectivity for 5-HT 1A receptors or α1-adrenergic receptors.

中文翻译：

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11C-O-甲基化芳基哌嗪作为潜在的血清素1A（5-HT1A）受体拮抗剂放射性示踪剂的合成，体外和体内评估。

血清素1A（5-HT1A）受体与几种精神病和神经退行性疾病的发病机制有关，从而促使体内正电子发射断层扫描（PET）神经影像学发展合适的放射性示踪剂。用于该靶标的金标准PET显像剂是[羰基-11C] WAY-100635，其通过具有技术挑战性的多步反应进行了标记，从而限制了其广泛使用。尽管已经开发出几种针对5-HT 1A受体的基于拮抗剂和激动剂的PET放射性示踪剂，但由于方法学上的挑战和/或非特异性结合，阻碍了它们的临床翻译。结果是，人们一直对开发新型的，选择性更高的5-HT1A PET示踪剂感兴趣，该示踪剂具有相对较容易和可靠的放射合成方法用于常规生产，并具有有利的代谢以促进示踪剂动力学建模。本研究的目的是开发和表征具有合适特征的放射性配体，以对大脑中的5-HT1A受体进行成像。本研究报告了三种候选5-HT1A受体拮抗剂DF-100（1），DF-300（2）和DF-400（3）的体外表征和放射性合成，以探讨其作为潜在PET示踪剂的适用性。1-3和相应的放射性标记前体的合成是由异烟酸，吡啶甲酸或吡啶甲酸腈实现的。体外结合研究证明了该化合物对5-HT1A受体的纳摩尔亲和力。除对α1-肾上腺素受体具有中等亲和力（比5-HT1A受体的效力低4-6倍）外，与其他生物胺，神经递质受体和转运蛋白的1-3结合可忽略不计。放射性配体[11C] 1-3通过相应的酚类前体的11C-O-甲基化而有效制备，其未经衰变校正的放射化学收率为7-11％，化学和放射化学纯度大于99％。在大鼠中进行的动态PET研究表明，大脑对[11C] 1和[11C] 2的摄取可忽略不计。相反，在SUV的早期高峰为4-5时，观察到大脑对[11C] 3的大量摄取。然而，基于区域分布（丘脑>海马体）和阻断研究，[11C] 3表现出显着的脱靶结合归因于α1-肾上腺素能受体。尽管放射性标记很有效，PET成像实验的结果限制了[11C] 3在体内定量5-HT1A受体的应用。然而，化合物3的衍生物可以提供对替代的PET放射性示踪剂的支架，其对5-HT 1A受体或α1-肾上腺素能受体具有改善的选择性。