Imaging vesicular monoamine transporters in the brain

大脑中囊泡单胺转运蛋白的成像

• 批准号: 6915711
• 负责人: Hank F Kung
• 金额: $ 36.82万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6915711
• 关键词: Huntington' s disease; Parkinson' s disease; baboons; binding sites; bioimaging /biomedical imaging; biological transport; brain imaging /visualization /scanning; chemical synthesis; drug design /synthesis /production; fluorine; glycoproteins; high performance liquid chromatography; laboratory rat; neural degeneration; neurotransmitters; pharmacokinetics; positron emission tomography; radiochemistry; radionuclides; radiotracer; technology /technique development; tetrabenazine

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.

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）对大脑中的囊泡单胺转运蛋白 2 (VMAT2) 位点进行成像，可用于诊断和监测神经退行性疾病，例如如帕金森病和亨廷顿病。此外，VMAT2结合位点的PET成像对于了解大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 是一种短寿命同位素，半衰期为 20 分钟，因此该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 诊所提供进行此类研究的便捷途径，建议使用半衰期为 110 分钟的 F-18 DTBZ 类似物。新的 VMAT2 显像剂可以由放射性制药厂生产并常规广泛分发。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、放射性标记和拆分。将通过使用体外结合测定比较结合亲和力来选择和优化它们。将确定静脉注射示踪剂后正常和病变大鼠脑中的体内生物分布研究。将针对选定的候选者对非人类灵长类动物大脑中 VMAT2 的体内 PET 成像研究和动力学模型进行评估。最终，预计将在该项目的第三年年底开发出用于 I 期临床试验的 VMAT2/PET 显像剂。该项目的目标是解决为常规临床使用提供有效的 PET 示踪剂的问题。如果成功开发，所提出的新型示踪剂可能会对各种脑功能异常和与单胺神经递质储存变化相关的疾病的诊断产生重大影响。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。 结合两个实验室的实力将大大提高实现该项目提出的目标的机会。