NON-CATECHOLIC L-DOPA ANALOGS

本研究的主要目的是开发新的非 儿茶酚化合物，这将是有用的示踪剂，用于估计 中枢神经系统中的多巴胺能活性。 溴化和 邻-L-酪氨酸和间-L-酪氨酸和非儿茶酚的氟化类似物 L-二羟基苯丙氨酸、2，4-L-多巴、2，5-L-多巴、2，6-L-多巴和 3，5-L-多巴，将制备和表征化学，生物化学和 使用常规方法进行检查。这些化合物不会 儿茶酚-O-甲基-转移酶（COMT）的底物，因为每一个la K 必需的englomerate部分。然而，这些化合物预计将恢复 n 与（1）通过载体的脑摄取有关的重要多巴胺性质 通过血脑屏障介导的转运，（2）区域性 选择性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）氧化代谢， 排泄由于COMT代谢途径被阻断， 与多巴胺相比会形成。这将是一个优势，因为它 可以简化活体大脑中多巴胺周转的评估。 无创估计中枢神经系统多巴胺周转可能是可能的， 定量放射性核素成像，例如PET或SPECT。评估 多巴胺活性可用于（1）临床前的常规诊断 帕金森病（PD）和其他多巴胺相关疾病，（2） 监测这些多巴胺相关疾病的治疗，（3）获得 深入了解左旋多巴不完全成功的根本原因 PD治疗，包括运动障碍和给药结束失败，和（4） 监测新的PD疗法，如神经组织自体移植。 在评价这些非儿茶酚类化合物作为多巴胺 示踪剂，有关结构要求的重要信息， 将获得参与CNS多巴胺合成和代谢的酶。 此外，深入了解运输系统的结构要求 通过血脑屏障，也需要囊泡 多巴胺神经元中的储存。 这反过来可能导致 更好地理解结构活性关系，这可能有助于 涉及中枢神经系统疾病的治疗剂的开发 多巴胺，如PD。

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.