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

18F-β-内啡肽成像：阿片肽放射性示踪剂的转化研究

• 批准号: 7873883
• 负责人: EDUARDO R BUTELMAN
• 金额: $ 25.35万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7873883
• 关键词: Absence of pain sensation; Adrenal Glands; Affect; Agonist; Alcohol dependence; Amino Acids; Analytical Chemistry; Benzaldehyde; Binding; Blood; Blood - brain barrier anatomy; Brain; Characteristics; Chemistry; Chronic; Cocaine; Collaborations; Complement; Development; Drug Addiction; Endocrine; Endorphins; Evaluation; Functional disorder; Future; Genetic Variation; Goals; Health Care Costs; Heroin; Hormones; Human; Hypothalamic structure; Image; Individual; Investigation; Knowledge; Label; Laboratories; Ligands; Macaca mulatta; Mediating; Medicine; Methodology; Methods; Modification; Morbidity - disease rate; Morphine; Naltrexone; Narcotic Antagonists; Nature; Neuropeptide Receptor; Neuropeptides; Neurosecretory Systems; Opiates; Opioid; Opioid Analgesics; Opioid Peptide; Opioid Receptor; Orthologous Gene; Oxycodone; Pain; Pathway interactions; Peptides; Peripheral; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Pituitary Gland; Positron-Emission Tomography; Process; Public Health; Radioisotopes; Radiolabeled; Regulation; Scheme; Signal Transduction; Single Nucleotide Polymorphism; Site; Staging; Stress; Structure-Activity Relationship; System; Work; addiction; analog; base; beta-Endorphin; carfentanil; clinically relevant; design; endogenous opioids; hormone analog; hypothalamic-pituitary-adrenal axis; in vivo; innovation; multidisciplinary; naltrindole; neuroimaging; nonhuman primate; novel; novel strategies; opioid abuse; prescription opioid; public health relevance; radiochemical; radiotracer; receptor; small molecule; translational study

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.

描述(由申请人提供)：这项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，翻译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，涉及合作PI在多肽化学、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专业知识，以及在放射化学合成、PET成像及其分析方面的指导和合作。β-内啡肽是5-阿片受体(MOP-r)的主要内源性激动剂，是海洛因等成瘾阿片类药物以及羟考酮和吗啡等处方阿片类止痛药的靶标。MOP-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)应激轴，这是成瘾状态的病理生理学的一部分。因此，作为一个长期目标，这种放射性示踪剂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MOP-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，来补充目前可用的小分子阿片类放射性示踪剂所获得的现有知识。这种变化可以在中枢或外周疼痛通路、HPA应激轴或血脑屏障中进行调节。目的1利用一种新颖的放射化学合成方法合成和优化一种新型的18F-b-内啡肽放射性示踪剂，并对其在非人类灵长类动物PET扫描中的外周、下丘脑和可能的中枢神经系统的其他部分的基本分布进行翻译相关性研究。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，特别是阿片受体的选择性和跨血脑屏障的分布。意义和影响：放射性标记-内啡肽的特定氨氧基衍生物的新策略也将在神经成像中产生更广泛的影响，因为它适用于其他神经肽和多肽激素及其类似物。18F-内啡肽作为成瘾和止痛药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直接研究内源性阿片类药物在成瘾和疼痛状态下的调节和分布，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，以及与外源化合物(包括滥用的阿片类药物)相比，内源性阿片神经肽药理的独特方面。在未来的研究中，这种放射性示踪剂将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MOP-r的单核苷酸多态(SNP)(人类的A118G及其建议的非人类灵长类直系同源基因)。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。 公共卫生相关性：这项I/START提案的主要目标是利用创新的放射化学合成方法，以内源性(即天然)阿片神经肽b-内啡肽为基础，翻译开发一种新型的PET神经成像放射性示踪剂。这种神经肽是一种主要的内源性化合物，作用于阿片受体(如5-阿片受体)，是滥用阿片类药物(如海洛因)以及主要处方阿片类止痛药(如羟考酮、吗啡)的靶标。这种新型神经肽放射性示踪剂的开发将极大地扩展我们在体内成像b-内啡肽/阿片受体系统在成瘾和疼痛状态下的功能的能力，这些状态会导致大量的发病率和公共卫生成本。