Imaging vesicular monoamine transporters in the brain

描述（由申请人提供）：用[C-11]DTBZ（二氢四苯那嗪）结合PET（正电子发射断层扫描）对脑内水泡单胺转运蛋白2 （VMAT2）部位进行成像，有助于诊断和监测神经退行性疾病，如帕金森病和亨廷顿病。此外，VMAT2结合位点的PET成像对于理解单胺在大脑中的调节机制及其与药物滥用和精神疾病的关系也很重要。由于C-11是一种半衰期为20分钟的短同位素，因此这种示踪剂的实用性受到现场回旋加速器和熟练研究人员团队的限制。为了克服使用这种非常有用的示踪剂的技术障碍，并为PET诊所提供进行此类研究的现成途径，提出了半衰期为110分钟的F-18 DTBZ类似物。新的VMAT2显像剂可由放射性制药公司生产并在常规基础上广泛分发。提出了新型F-18标记DTBZ衍生物的非对映体和对映体的合成、放射性标记和分辨方法。通过体外结合实验比较其结合亲和力，对其进行筛选和优化。对正常大鼠和损伤大鼠静脉注射示踪剂后进行脑内生物分布研究。在非人类灵长类动物的体内PET成像研究和VMAT2在大脑中的动力学建模将对选定的候选动物进行评估。最终，预计VMAT2/PET显像剂将在本项目第三年结束时开发用于I期临床试验。该项目的目的是解决一个问题，提供有效的PET示踪剂常规临床使用。如果开发成功，所提出的新型示踪剂可能对各种脑功能异常和与单胺类神经递质储存改变相关的疾病的诊断有很大影响。这是宾夕法尼亚大学PI研究小组和密歇根大学Michael Kilbourn博士的合作项目。结合两个实验室的实力将大大提高实现本项目所提出的目标的机会。

DESCRIPTION (provided by applicant): Imaging of vesicular monoamine transporter 2 (VMAT2) sites in the brain by [C-11]DTBZ (dihydrotetrabenazine) in conjunction with PET (positron emission tomography) is useful in the diagnosis and monitoring of neurodegenerative diseases such as Parkinson's and Huntington's diseases. In addition, PET imaging of VMAT2 binding sites is also important for understanding the mechanisms of regulation of monoamines in the brain and its relationship with drug abuse and psychiatric disorders. Since C-11 is a short lived isotope with a half-life of 20 minutes the usefulness of this tracer is limited by a requirement for an onsite cyclotron and a team of skilled researchers. To overcome the technical barrier of using this otherwise very useful tracer and to provide ready access for PET clinics to perform this type of study, F-18 DTBZ analogs with a half-life of 110 min are proposed. The new VMAT2 imaging agents could be manufactured by radiopharmacies and distributed widely on a routine basis. Synthesis, radiolabeling and resolution of diastereomers and enantiomers of novel F-18 labeled DTBZ derivatives are proposed. They will be selected and optimized by comparing binding affinity using in vitro binding assay. In vivo biodistribution study in the brain of normal and lesioned rats after iv injection of the tracers will be determined. In vivo PET imaging study and kinetic modeling of VMAT2 in the brain of non-human primates will be evaluated for selected candidates. Ultimately, it is expected that a VMAT2/PET imaging agent will be developed for phase I clinical trial by the end of the third year of this project. The objective of this project is to solve a problem in supplying an effective PET tracer for routine clinical use. If successfully developed, the proposed novel tracers may have a high impact on the diagnosis of various abnormalities of brain function and diseases related to changes of the storage of monoamine neurotransmitters. This is a collaborative project between the research groups of the PI in University of Pennsylvania and Dr. Michael Kilbourn, University of Michigan. Combining the strength of two laboratories will greatly enhance the chance of reaching the goals proposed in this project.