A Novel VMAT 2 Radioligand for Imaging Parkinson's

描述(由申请人提供)： 帕金森氏病(PD)的临床特征是运动迟缓、僵硬、震颤和步态障碍，进展缓慢，持续多年。多巴胺神经元的病理生理损失是这种疾病的一个标志，并指导了减轻症状的治疗。帕金森病的尸检研究表明，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。这些靶标包括多巴胺转运体(DAT)和囊泡单胺转运体2(VMAT 2)。这两个靶点被认为参与了帕金森病神经退行性变的进程。使用正电子发射断层扫描(PET)和单光子发射断层扫描(SPECT)的神经成像技术已被用于利用这些多巴胺细胞丢失的标记物更好地描述帕金森病的活体疾病过程。VMAT2的一个突触前细胞标记物是L lc标记的四苯肼。由于进行大规模临床评估的后勤困难，该示踪剂已用于数量有限的帕金森病患者。用于标记化学部分的L液晶核素的半衰期很短(20REE)，这限制了示踪剂的广泛使用和商业应用。这一前景看好的临床和研究工具的广泛使用将需要一种更实用的放射性同位素。在这项应用中，我们建议开发一种更长的半衰期(123I，半衰期13h)SPECT放射性示踪剂，用于PD患者的VMAT-2显像。我们的目标是制备一种放射性碘标记的四苯并嗪类似物。将为该示踪剂开发一种简单的放射化学合成方法。我们将评估新开发的化合物的体外性质。此外，我们将使用啮齿动物评估其在体内的生物学特性，包括对靶点的选择性、在脑组织中的穿透性、在小鼠药物干预期间放射性配基的药效学特性。

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.