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）：此I/开始提案的主要目标是基于内源性阿片类神经肽B-内啡肽的新型PET放射性示踪剂的转化开发，使用创新和快速的18F放射性标记策略。这是一个多学科的过渡项目，涉及非人类灵长类动物中肽化学，分析化学和体内阿片类药物药理学方面的专业知识，以及放射化学合成，宠物成像及其分析的指导和协作。 B-内啡肽是5-阿片类受体（MOP-R）的主要内源性激动剂，这是成瘾性阿片类药物的靶标，例如海洛因和处方阿片类镇痛药，例如羟考酮和吗啡。 MOP-R也与可卡因和酒精成瘾的下游作用相关，还调节下丘脑 - 垂体 - 肾上腺（HPA） - 压力轴，这是成瘾性态理生理学的一部分。因此，作为一个长期目标，可以使用这种放射性示例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。通过揭示内啡肽分布，药效学或由于成瘾或疼痛状态引起的系统水平功能的变化，这种新的放射性示例将与当前可用的小分子阿片类药物放射性示例获得的可用知识相互补充。这种改变可以在中央或外围疼痛途径，HPA压力轴或血脑屏障中介导。 AIM 1专注于使用创新的放射化学合成的新型18F-B-内啡肽放射性培训的合成和优化，及其在非人类灵长类动物的PET扫描中的外围，下丘脑以及PET扫描中CNS的基本分布，以进行转化相关性。然后，AIM 2将确定该放射性示踪剂的关键药效​​和分布特征，尤其是阿片受体的选择性和在血脑屏障中的分布。意义和影响： - 内啡肽的特定氨基氧化衍生物的放射性标记的新策略也将在神经成像中产生更大的影响，因为它适用于其他神经肽和肽激素及其类似物。 18F-端代素作为成瘾和止痛药的成像剂具有相当大的潜在意义。特别是，这种放射性示例可以直接研究成瘾和疼痛状态中的内源性阿片类药物调节和分布，以及HPA压力轴的相关功能变化。与外源性化合物（包括滥用的阿片类药物）相比，这将包括内分泌B-内啡肽的分布和命运以及内源性阿片类神经肽药理学的独特方面。在未来的研究中， - 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（人类A118G）的单个核苷酸多态性（SNP），及其拟议的非人类灵长类动物直立性的原始原理）。该SNP影响成瘾和疼痛状态以及HPA轴功能的人类脆弱性。 公共卫生相关性：I/开始提案的主要目标是使用创新的放射化学合成方法基于内源性（即天然）阿片神经肽B-内啡肽的新型PET神经影像学的转化。该神经肽是作用于阿片类受体（例如5-粘体受体）的主要内源性化合物，它是滥用鸦片剂（例如海洛因）的靶标，以及主要的处方阿片类镇痛药（例如，羟考酮，吗啡）。这种新颖的神经肽放射性示例的发展将大大扩展我们在体内形象形象的能力，在上瘾和疼痛状态下，B-内啡肽 /阿片类受体系统的功能，这会导致巨大的发病率和公共卫生成本。