NON-CATECHOLIC L-DOPA ANALOGS

本研究的主要目的是开发新型非金属材料。 儿茶酚类化合物可作为示踪剂用于估计 中枢神经系统中的多巴胺能活动。溴化和 邻位-L-酪氨酸和间-L-酪氨酸的氟化类似物及其非儿茶性 L-二羟基苯丙氨酸、2，4-L-多巴、2，5-L-多巴、2，6-L-多巴和 将制备3，5-L-多巴，并对其进行化学、生化和化学结构表征. 使用传统的药理学方法。这些化合物不会是 儿茶酚-O-甲基转移酶(COMT)的底物 K 必需的烯二醇部分。然而，这些化合物预计会被重复使用 N 与(1)通过载体的大脑摄取有关的重要多巴胺特性 通过血脑屏障的调节转运，(2)区域转运 选择性ON与多巴胺神经支配一致，(3)囊泡储存 多巴胺神经元，(4)调节释放和(5)氧化和代谢 排泄物。由于COMT代谢途径被阻断，较少的代谢物 会比多巴胺更容易形成。这将是一个优势，因为它 可能会简化对活体大脑中多巴胺周转的评估。 无创性地估计中枢神经系统多巴胺周转可能通过 定量放射性核素成像，如正电子发射计算机断层扫描或SPECT。评估 多巴胺活性可用于(1)临床前的常规诊断 帕金森氏病(PD)和其他与多巴胺相关的疾病(2) 监测这些多巴胺相关疾病的治疗，(3)获得 洞察L-多巴未获成功的深层原因 帕金森病的治疗，包括运动障碍和剂量结束失败，以及(4) 监测帕金森病的新疗法，如自体神经组织移植。 在评估这些非儿茶酚化合物作为多巴胺的适宜性时 示踪剂，关于结构要求的重要信息 将获得参与中枢神经系统多巴胺合成和代谢的酶。 此外，对运输系统结构要求的洞察 通过血脑屏障，也需要水泡 结果就是多巴胺神经元的储存。这反过来可能会导致 更好地理解结构活性关系，这可能有助于 中枢神经系统疾病治疗药物的研究进展 多巴胺，如帕金森病。

The main objective of this research is the development of novel non- catecholic compounds which would be useful as tracers for the estimation of dopaminergic activity in the central nervous system. Brominated and fluorinated analogs of o-L-tyrosine and m-L-tyrosine and non-catecholic L-dihydroxyphenylalanines, 2,4-L-dopa, 2,5-L-dopa, 2,6-L-dopa and 3,5-L-dopa, will be prepared and characterized chemically, biochemically an pharmacologically using conventional methods. These compounds would not be substrates of the enzyme catechol-o-methyl-transferase (COMT) since each la k the essential enediol moiety. However, these compounds are expected to reta n important dopamine properties related to (1) cerebral uptake via carrier mediated transport through the blood brain barrier, (2) regionally selective on consistent with dopamine innervation, (3) vesicular storage in dopamine neurons, (4) regulated release and (5) metabolism by oxidation and excretion. Since the COMT metabolic pathway is blocked, less metabolites would be formed compared to dopamine. This would be an advantage since it may simplify the assessment of dopamine turnover in the living brain. Non-invasive estimation of CNS dopamine turnover may be possible by quantitative radionuclide imaging such as PET or SPECT. Assessment of dopamine activity may be useful in (1) the routine diagnosis of preclinical Parkinson's disease (PD) and other dopamine-related disorders, (2) monitoring therapy of these dopamine-related disorders, (3) gaining insights into the underlying causes of the incomplete success of L-dopa therapy in PD including dyskinesias and end-of-dose failures, and (4) in monitoring novel PD therapies such as neural tissue autotransplantation. In evaluating the suitability of these non-catecholic compounds as dopamine tracers, significant information on the structural requirements of the enzymes involved in CNS dopamine synthesis and metabolism will be obtained. Further, insights into the structural requirements of the transport system through the blood brain barrier, and also requirements for vesicular storage in dopamine neurons would result. This in turn may lead to a better understanding of structure activity relationships which may aid in the development of therapeutic agents for disorders involving central dopamine such as PD.