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

描述（由申请人提供）：本I/START提案的主要目标是使用创新和快速的18 F放射性标记策略，基于内源性阿片神经肽b-内啡肽的新型PET放射性示踪剂的转化开发。这是一个多学科的过渡项目，涉及肽化学，分析化学和非人灵长类动物体内阿片受体药理学方面的共同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。β-内啡肽是δ-阿片受体（MOP-r）的主要内源性激动剂，其是成瘾性阿片类药物（如海洛因）和处方阿片类镇痛药（如羟考酮和吗啡）的靶标。MOP-r还显着参与可卡因和酒精成瘾的下游效应，并且还调节下丘脑-垂体-肾上腺（HPA）-应激轴，这是成瘾状态病理生理学的一部分。作为一个长期的目标，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β-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MOP-r中的个体遗传变异而引起的内啡肽分布、药效学或系统水平功能的变化，来补充利用目前可用的小分子阿片类放射性示踪剂获得的可用知识。这种改变可以在中枢或外周疼痛通路、HPA-应激轴或血脑屏障中介导。目的1的重点是合成和优化的一种新的18F-b-内啡肽放射性示踪剂，使用创新的放射化学合成，其基本分布在外周，下丘脑，并可能在非人类灵长类动物的PET扫描的CNS的其他部分，翻译相关性。然后，目标2将确定这种放射性示踪剂的关键药效学和分布特征，特别是阿片受体选择性和穿过血脑屏障的分布。意义和影响：放射性标记β-内啡肽的特定氨基-氧基衍生物的新策略也将在神经成像中具有更广泛的影响，因为它适用于其他神经肽和肽激素及其类似物。18F-内啡肽作为成瘾和疼痛医学的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允许直接调查成瘾和疼痛状态下的内源性阿片调节和分布，以及HPA-应激轴的相关功能变化。这将包括内分泌B -内啡肽的分布和转归，以及与外源性化合物（包括滥用阿片类药物）相比，内源性阿片类神经肽药理学的独特方面。潜在的独特方面-内啡肽的功能，以直接评估与这种放射性示踪剂在未来的研究包括血脑过程，和直接评估的单核苷酸多态性（SNP）MOP-r（A118 G在人类中，其提出的非人类灵长类动物直系同源）。这种SNP影响个体在成瘾和疼痛状态中的脆弱性，以及HPA轴功能。 公共卫生相关性：该I/START提案的主要目标是基于内源性（即，天然）阿片类神经肽，b-内啡肽，使用创新的放射化学合成方法。这种神经肽是作用于阿片受体的主要内源性化合物（例如，5-阿片受体），其是滥用的阿片类药物的靶点（例如，海洛因），以及主要的处方阿片类镇痛药（例如，羟考酮、吗啡）。这种新的神经肽放射性示踪剂的发展将大大扩展我们的能力，在体内成像的功能的b-内啡肽/阿片受体系统在成瘾和疼痛状态，条件，导致大量的发病率和公共卫生成本。

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.