Imaging vesicular monoamine transporters in the brain

描述（由申请人提供）：通过[C-11]DTBZ（二氢丁苯那嗪）结合PET（正电子发射断层扫描）对脑中囊泡单胺转运蛋白2（VMAT 2）位点进行成像，可用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，VMAT 2结合位点的PET成像对于理解脑中单胺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分钟的短寿命同位素，因此这种示踪剂的有效性受到现场回旋加速器和熟练研究人员团队的要求的限制。为了克服使用这种非常有用的示踪剂的技术障碍，并为PET诊所进行这种类型的研究提供方便，提出了半衰期为110分钟的F-18 DTBZ类似物。新的VMAT 2显像剂可以由放射性药物制造，并在常规基础上广泛分布。对新型氟-18标记DTBZ衍生物的非对映体和对映体的合成、标记和拆分进行了研究。将通过使用体外结合试验比较结合亲和力来选择和优化它们。将测定静脉注射示踪剂后在正常和病变大鼠脑中的体内生物分布研究。将对选定的候选者进行体内PET成像研究和非人灵长类动物脑中VMAT 2的动力学建模。最终，预计在该项目的第三年年底，将开发出用于I期临床试验的VMAT 2/PET显像剂。本项目的目的是解决一个问题，在提供一个有效的PET示踪剂的常规临床使用。如果成功开发，所提出的新型示踪剂可能对诊断各种脑功能异常和与单胺神经递质储存变化相关的疾病具有很高的影响。这是宾夕法尼亚大学PI和密歇根大学Michael Kilbourn博士研究小组之间的合作项目。 结合两个实验室的力量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.