Novel VMAT 2 Radioligand for Imaging Parkinson's

描述（由申请人提供）： 帕金森病（PD）的临床特征是运动迟缓、僵硬、震颤和步态障碍，其进展缓慢多年。多巴胺神经元的病理生理学损失是这种疾病的标志，并指导了减轻症状的治疗。帕金森病的死后研究表明，多巴胺神经元和位于垂死神经元末端的分子靶点显着减少。这些靶点包括多巴胺转运蛋白（DAT）和囊泡单胺转运蛋白2型（VMAT 2）。这两个靶点与介导PD中神经退行性过程的进展有关。使用正电子发射断层扫描（PET）和单光子发射断层扫描（SPECT）的神经成像技术已在更好地表征疾病的过程中，在PD体内使用这些标记多巴胺细胞损失。VMAT 2的一种突触前细胞标志物是11c标记的丁苯那嗪。由于进行大规模临床评价的后勤困难，该示踪剂已用于有限数量的PD患者。示踪剂的广泛使用和商业应用受到用于标记化学部分的11c核素的非常短的半衰期（20 μ π ι）的限制。这种有前途的临床和研究工具的广泛使用将需要更实用的放射性同位素。在此应用中，我们建议开发一种更长的半衰期（123I，半衰期13小时）SPECT放射性示踪剂VMAT 2成像在PD患者。我们的目标是制备放射性碘标记的丁苯那嗪类似物。一个简单的放射化学合成将开发这种示踪剂。我们将评估新开发的化合物的体外特性。此外，我们将使用啮齿类动物评估其体内生物学特性，包括对靶位点的选择性、脑组织中的迁移率、小鼠药理学干预期间放射性配体的药效学特性。

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is clinically characterized by bradykinesia, rigidity, tremor, and gait disturbance that progresses slowly over many years. The pathophysiological loss of dopamine neurons is a hallmark of this disorder and has guided treatments for reducing symptoms. Post mortem studies in PD demonstrate a marked reduction of dopamine neurons and the molecular targets located on terminals of dying neurons. These targets include the dopamine transporter (DAT) and vesicular monoamine transporters type 2 (VMAT 2). These two targets have been implicated in mediating the progression of the neurodegenerative process in PD. Neuroimaging techniques using positron emission tomography (PET) and single photon emission tomography (SPECT) have been useful in better characterizing the disease process in vivo in PD using these markers of dopamine cell loss. One presynaptic cell marker for VMAT 2 is l lc labeled tetrabenazine. This tracer has been used in a limited number of PD patients owing to the logistical difficulty in performing large-scale clinical evaluations. The widespread use and commercial application of the tracer is limited by the very short half-life of the l lc nuclide (20 rain) used to tag the chemical moiety. The wider use of this promising clinical and research tool will require a more practical radioisotope. In this application, we propose to develop a longer half-life (123I, half life 13 h) SPECT radiotracer for VMAT 2 imaging in PD patients. Our goal is to prepare a radioiodinated tetrabenazine analog. A simple radiochemical synthesis will be developed for this tracer. We will assess the in vitro properties of newly developed compounds. In addition, we will assess its biological properties in vivo using rodents that will include selectivity for the target site, penetrance in brain tissue, pharmacodynamic properties of the radioligand during pharmacological interventions in mice.