18F-AV-133, A Novel Radiopharmaceutical for Differential Diagnosis of Dementia

描述(由申请人提供)：痴呆症及其最常见的亚型阿尔茨海默病(AD)、路易体痴呆(DLB)和血管性痴呆是一个非常严重的医学和社会问题。许多药物和候选药物的出现干扰了特定类型痴呆症的疾病机制，因此早期区分各种形式至关重要。有用的诊断工具将使患者有可能选择最合适的药物方案，避免接触潜在有害药物，并监测疾病修正药物的疗效。脑成像技术为痴呆的鉴别诊断和疾病进展监测提供了一种非侵入性的工具。我们和其他人一直在开发放射性药物，允许检测AD典型的淀粉样蛋白沉积。我们的努力集中在用于PET成像的18F标记化合物上，目标是以最低的成本广泛提供成像诊断。我们现在建议临床开发一种新的放射性配基，用于DLB与AD的鉴别诊断以及监测DLB的疾病进展。18F-AV-133是囊泡单胺转运体VMAT2的高选择性配体，被认为是反映DLB中已知退行性变的多巴胺能神经元功能完整性的最佳标志。我们的建议验证了这样的假设，即VMAT2的成像为多巴胺能神经元退化提供了一个有用的生物标记物，它可以与淀粉样斑块成像协同结合，为痴呆患者的分类产生强大的诊断工作。我们建议进行两项临床研究，以确定18F-AV-133作为DLB诊断显像剂的安全性和概念性。公共卫生相关性：拟议的第一阶段研究的成功完成将为临床诊断和监测路易体痴呆(DLB)、阿尔茨海默病(AD)和一般痴呆症的疾病进展提供关键的一步。这些研究将确定一种诊断工具，使医生能够指导患者使用最合适的药物方案，并防止患者接触到潜在的有害药物。此外，由此产生的诊断工具将使在体内监测分子水平的治疗效果成为可能，从而大大有助于疾病修正药物的开发。这种诊断工具将为社会带来重大的技术和医疗效益。

DESCRIPTION (provided by applicant): Dementia, with its most prevalent subforms Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and vascular dementia, is a very substantial medical and societal problem. The emergence of many drugs and drug candidates that interfere with the disease mechanism of specific types of dementia makes it crucial to distinguish early between the various forms. Useful diagnostic tools will make it possible to direct patients to the most appropriate drug regimen, to avoid exposure to potentially harmful drugs, and to monitor the efficacy of disease-modifying drugs. Brain imaging techniques provide a non-invasive tool for differential diagnosis and monitoring of disease progression of dementia. We and others have been developing radiopharmaceuticals that allow detection of A amyloid deposits typical for AD. Our efforts have focused on 18F-labeled compounds for PET imaging, with the goal that the imaging diagnostics can be made widely available at minimal costs. We now propose the clinical development of a new radioligand for the differential diagnosis of DLB from AD as well as the monitoring of DLB disease progression. 18F-AV-133 is a highly selective ligand for the vesicular monoamine transporter VMAT2, believed to be the best marker for the functional integrity of dopaminergic neurons which are known to degenerate in DLB. Our proposal tests that hypothesis that imaging of VMAT2 provides a useful biomarker for dopaminergic neuron degeneration, which can be synergistically combined with amyloid plaque imaging to generate a powerful diagnostic work up for classification of dementia patients. We propose to conduct two clinical studies to establish safety and proof-of-concept for 18F-AV-133 as a diagnostic imaging agent for DLB. PUBLIC HEALTH RELEVANCE: Successful completion of the proposed phase I studies will provide a key step towards the provision of diagnostic tools for the clinical diagnosis and monitoring of disease progression of dementia with Lewy bodies (DLB), Alzheimer's disease (AD) and dementias in general. The studies will identify a diagnostic tool to allow the physicians to direct patients towards the most appropriate drug regimen and prevent that the patients are exposed to potentially harmful drugs. Furthermore, the resulting diagnostic tools will help significantly in the development of disease-modifying drugs, by making it possible to monitor treatment efficacy at the molecular level in vivo. Such a diagnostic tool will represent a significant technological and medical benefit to society.