ENZYME TARGETED IMAGING AGENTS FOR NEUROPSYCHIATRY

PET显像剂针对合成中的限速酶 神经递质的多巴胺和5-羟色胺将被开发出来 在体内作为神经递质评估的示踪剂 流动率。目标酶是酪氨酸羟化酶(TH)和 色氨酸羟基酶(TrpH)是细胞内的限速酶 多巴胺和5-羟色胺的生物合成。α-氟甲基-p- 酪氨酸和α-氟甲基-L色氨酸均为Trp 分别为底物。这两种化合物都是通过它们的 各自的羟基化酶生成的产物不可逆转地结合 酶在下一步的合成中各自 神经递质。这些化合物的双重酶激活将 用11C标记的FMPT和FMTrp作为 因此，PET示踪剂可以简化多巴胺和5-羟色胺的定量 神经元活动自累积的捕获量 放射性将依赖于酶的活性，由 神经元活动。~(14)C或~(14)C的时间进程、生物分布和代谢 ~3H标记的FMPT和FMTrp将在啮齿类动物身上进行评估。初步 使用正电子发射断层扫描进行验证将使用恒河猴来验证时间 脑摄取的过程、特异性和非特异性定位及 通行证。这些示踪剂随后将在老鼠身上进一步评估，如果 通过使用14C或~3H标记化合物的放射自显影，是必要的。 由于多巴胺和5-羟色胺都参与了神经精神病学 疾病，无创评估神经元周转率使用 这种PET方法可能会提供有用的数据，以更好地理解 这些化学物质传递给健康和疾病。潜在的应用 在这个项目中开发的PET技术的一部分包括早期诊断 神经精神疾病的治疗方法的开发和监测 神经退行性疾病，如帕金森氏病和精神病学 精神分裂症、抑郁症、情感障碍和 攻击性、冲动和暴力行为。在本报告中所作的观察 研究可能会深入了解这些疾病的病因，这可能 导致更好的预防和治疗方法。

PET imaging agents directed at the rate limiting enzymes in the synthesis of the neurotransmitter dopamine and serotonin will be developed and evaluated as tracers in the assessment, in vivo, o neurotransmitter turnover rate. The targeted enzymes are tyrosine hydroxylase (TH) and tryptophan hydroxylase (TrpH) which are the rate limiting enzymes in the biosynthesis of dopamine and serotonin respectively. alpha-Fluoromethyl-p- tyrosine (FMPT) and alpha-fIuoromethyl-L-tryptophan (FMTrp) are TH an TrpH substrates, respectively. Both compounds are transformed by their respective hydroxylating enzyme into products which bind irreversibly the enzyme in the next step in the synthesis of their respective neurotransmitter. The dual enzyme activation of these compounds will result in high neuronal selectivity The use 11C-labelled FMPT and FMTrp as PET tracers may therefore simplify quantitation of dopamine an serotonin neuronal activity since the amount of the accumulated trapped radioactivity would be dependent on the enzyme activity as regulated by neuronal activity. Time course, biodistribution and metabolism of 14C or 3H Iabelled FMPT and FMTrp will be assessed in rodents. Preliminary validation using PET will be done using rhesus monkeys to verify the time course of brain uptake, specific and non-specific localization an clearance. These tracers will then be further evaluated in rats, if warranted, by autoradiography using 14C or 3H Iabelled compounds. Since both dopamine and serotonin are involved in neuropsychiatric disorders, the non-invasive assessment of neuronal turnover rate using this PET method may provide useful data to better understand the role of these chemical transmitters to health and disease. Potential applications of the PET technique developed in this project include early diagnosis of neuropsychiatric diseases, development and monitoring of therapies for neurodegenerative diseases such Parkinson's disease and psychiatric disorders such as schizophrenia, depression, affective disorders, and aggressive, impulsive and violent behaviors. Observations made in this research may give insight into the etiology of these disorders which may lead to better approaches to their prevention and therapy.