Halopiperidines for imaging of monoamine transporters

描述（由申请人提供）：单胺转运体是治疗、诊断和监测许多中枢神经系统疾病状态的重要靶点。预计对多巴胺转运体（DAT）表现出高亲和力和选择性的显像剂将满足许多未被满足的需求，包括用于帕金森病（PD）、ADD/ADHD、抑郁症和可卡因滥用。此外，对血清素或去甲肾上腺素转运体表现出高亲和力和选择性的显像剂也同样适用于抑郁综合征和相关疾病的诊断和监测。然而，许多研究已经报道了用于DAT的放射性配体的设计，但尚未披露具有广泛应用所需的良好成像特性的试剂。关于血清素（5-HTT）和去甲肾上腺素（NET）转运体的特异性放射性配体的报道较少。在此，我们提出了合理的设计和合成一系列卤化哌啶作为潜在的放射性示踪剂，利用PET和SPECT成像单胺转运体。这些研究利用我们多功能和高效的哌啶药效团，利用哌啶对映异构体/异构体的不同结构活性关系，轻松制备高选择性单胺转运体配体。以这种方式，预计这项工作将导致鉴定新的放射性药物，这些药物可以用正电子发射元件进行PET标记，或用单光子发射元件进行SPECT标记。这些放射性药物将广泛用于中枢神经系统疾病的诊断和治疗干预的监测。

DESCRIPTION (provided by applicant): The monoamine transporters are important targets for therapy, diagnosis and monitoring of a number of CNS disease states. It is expected that imaging agents that exhibit high affinity and selectivity for the dopamine transporter (DAT) would fulfill a number of unmet needs including use for Parkinson's disease (PD), ADD/ADHD, depression and cocaine abuse. Additionally, imaging agents that exhibit high affinity and selectivity for either the serotonin or norepinephrine transporters would similarly be of utility for the diagnosis and monitoring of depressive syndromes and related disorders. While, many studies have reported the design of radioligands for the DAT no agents have been disclosed that exhibit favorable imaging properties that are required for widespread utilization. Fewer reports are available on specific radioligands for the serotonin (5-HTT) and norepinephrine (NET) transporters. Herein, we propose the rational design and synthesis a series of halogenated piperidines as potential radio-tracers for imaging of the monoamine transporters utilizing PET and SPECT. These studies utilize our versatile and efficient piperidine pharmacophore for the facile preparation of highly selective monoamine transporter ligands exploiting the divergent structure activity relationships for the enantiomers/isomers of the piperidine. In this manner it is anticipated that this work will result in the identification of new radiopharmaceuticals that can be labeled with positron emitting elements for PET, or single photon emitting elements for SPECT. These radiopharmaceuticals would be of wide spread use for both the diagnosis of CNS disorders and the monitoring of therapeutic interventions.