18F-beta-Endorphin Imaging: Translational Study of an Opioid Peptide Radiotracer

描述（由申请人提供）：本I/START提案的主要目标是利用创新和快速的18F放射性标记策略，开发一种基于内源性阿片神经肽b-内啡肽的新型PET放射性示踪剂。这是一个多学科的过渡项目，涉及到肽化学、分析化学和非人类灵长类动物体内阿片受体药理学方面的合作pi的专业知识，以及放射化学合成、PET成像及其分析方面的指导和合作。b-内啡肽是5-阿片受体（MOP-r）的主要内源性激动剂，是海洛因等成瘾性阿片类药物和羟可酮、吗啡等处方阿片类镇痛药的靶点。mopp -r还显著参与可卡因和酒精成瘾的下游效应，并调节下丘脑-垂体-肾上腺(HPA)-压力轴，这是成瘾状态病理生理学的一部分。作为一个长期目标，这种放射性示踪剂因此可以用来确定成瘾或疼痛状态如何影响功能性b-内啡肽分布和受体药效学。这种新的放射性示踪剂将通过揭示由于成瘾或疼痛状态或由于mopp -r的个体遗传变异而导致的内啡肽分布、药效学或系统水平功能的变化，补充目前可用的小分子阿片样物质放射性示踪剂所获得的知识。这种改变可以介导中枢或外周疼痛通路、hpa -应激轴或血脑屏障。目的1主要研究一种新型18f -b-内啡肽放射性示踪剂的合成和优化，该示踪剂使用一种创新的放射化学合成方法，并在非人类灵长类动物的PET扫描中在外周、下丘脑和可能的中枢神经系统其他部分的基本分布，以获得翻译相关性。然后，Aim 2将确定该放射性示踪剂的关键药效学和分布特征，特别是阿片受体的选择性和在血脑屏障中的分布。意义和影响：对-内啡肽的特定氨基氧衍生物进行放射性标记的新策略也将对神经影像学产生更广泛的影响，因为它适用于其他神经肽和肽激素及其类似物。18F-内啡肽在成瘾和疼痛药物中作为显像剂具有相当大的潜在意义。特别是，这种放射性示踪剂可以直接研究成瘾和疼痛状态下内源性阿片样物质的调节和分布，以及hpa -应激轴的相关功能变化。这将包括内分泌b -内啡肽的分布和命运，以及与外源性化合物（包括滥用的阿片类药物）相比，内源性阿片类神经肽药理学的独特方面。在未来的研究中，使用该放射性示踪剂直接评估-内啡肽功能的潜在独特方面包括血脑过程，以及直接评估mopp -r（人类A118G，及其拟议的非人类灵长类同源物）中的单核苷酸多态性（SNP）。这种SNP影响个体在成瘾和疼痛状态下的脆弱性，以及hpa轴功能。

DESCRIPTION (provided by applicant): The main goal of this I/START proposal is the translational development of a novel PET radiotracer based on an endogenous opioid neuropeptide, b-endorphin, using an innovative and rapid 18F radiolabeling strategy. This is a multidisciplinary transitional project involving the expertise of the co-PIs in peptide chemistry, analytical chemistry, and in vivo opioid receptor pharmacology in non-human primates, as well as guidance and collaboration in radiochemical synthesis, PET imaging, and its analysis. b-endorphin is a major endogenous agonist at 5-opioid receptors (MOP-r), the target of addictive opioids such as heroin and prescription opioid analgesics such as oxycodone and morphine. MOP-r are also prominently involved in the downstream effects of cocaine and alcohol addiction, and also modulate the hypothalamic-pituitary-adrenal (HPA)-stress axis, which is part of the pathophysiology of addictive states. As a long-term objective, this radiotracer could therefore be used to determine how addiction or pain states affect functional b-endorphin distribution and receptor pharmacodynamics. This new radiotracer would complement the available knowledge obtained with currently available small molecule opioid radiotracers, by revealing changes in - endorphin distribution, pharmacodynamics, or systems level function due to addiction or pain states, or due to individual genetic variation in MOP-r. Such alterations can be mediated in central or peripheral pain pathways, in HPA-stress axis, or at the blood-brain barrier. Aim 1 focuses on the synthesis and optimization of a novel 18F-b-endorphin radiotracer using an innovative radiochemical synthesis, and its basic distribution in the periphery, hypothalamus, and possibly other parts of the CNS in PET scans in non-human primates, for translational relevance. Aim 2 would then determine key pharmacodynamic and distribution characteristics of this radiotracer, particularly opioid receptor selectivity and distribution across the blood-brain barrier. Significance and Impact: The novel strategy for radiolabeling a specific amino-oxy derivative of -endorphin would also have broader impact in neuroimaging as it is applicable to other neuropeptides and peptidic hormones and analogs thereof. 18F--endorphin has considerable potential significance as an imaging agent in addiction and pain medicine. In particular, this radiotracer could allow direct investigation of endogenous opioid regulation and distribution in addiction and pain states, as well as related functional changes in the HPA-stress axis. This would include the distribution and fate of endocrine b -endorphin, as well as unique aspects of endogenous opioid neuropeptide pharmacology, compared to that of exogenous compounds (including abused opioid drugs). Potentially unique aspects of -endorphin function to be directly evaluated with this radiotracer in future studies include blood-brain processes, and direct evaluation of a single nucleotide polymorphism (SNP) in MOP-r (A118G in humans, and its proposed non-human primate ortholog). This SNP affects individual human vulnerability in addiction and pain states, as well as HPA-axis function. PUBLIC HEALTH RELEVANCE: The main goal of this I/START proposal is the translational development of a novel PET neuroimaging radiotracer based on an endogenous (i.e., natural) opioid neuropeptide, b-endorphin, using innovative radiochemical synthesis methodology. This neuropeptide is a major endogenous compound acting at opioid receptors (e.g., the 5-opoid receptor), which are targets of abused opiates (e.g., heroin), as well as major prescription opioid analgesics (e.g., oxycodone, morphine). The development of this novel neuropeptide radiotracer will greatly expand our ability to image in vivo the function of the b-endorphin / opioid receptor system in addictive and pain states, conditions which cause massive morbidity and public health costs.