Development Of New Approaches To Neuroimaging with PET a

开发 PET 神经影像新方法

• 批准号: 6830622
• 负责人: ALANE S KIMES
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON DRUG ABUSE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6830622
• 关键词: analog; bioimaging /biomedical imaging; blood brain barrier; cannabinoid receptor; cannabinoids; clinical research; drug design /synthesis /production; human subject; hydropathy; magnetic resonance imaging; method development; neuroimaging; neuropharmacology; nicotine; nicotinic receptors; positron emission tomography; radiotracer; receptor expression; single photon emission computed tomography

PET Section The ability to image and quantify nicotinic receptors in human brain may be crucial to better understanding the neurobiology of smoking addiction. Analogs of A-85380 and A-84543 have been evaluated as imaging agents for nicotinic acetylcholine receptors (nAChRs) with positron emission tomography (PET) and single photon emission computed tomography (SPECT). Radiation dosimetry and toxicological studies in animals demonstrated the safety of 5-[I-125]iodo-A-85380 (5IA). In collaboration with Yale University, the SPECT studies with 5IA revealed that cerebral nAChRs can be quantified in human non-smoking volunteers. Similarly, the first human PET studies in non-smokers with 2-[F-18]fluoro-A-85380 (2FA) demonstrated the feasibility of quantitatively imaging nAChRs in the thalamus and visualizing these receptors in brain regions containing low to moderate receptor densities and that multiple studies on a single volunteer are possible within dosimetry limits. Additionally, the cardiovascular safety of 2FA in humans was established by demonstrating the lack of effects on blood pressure and electrocardiograms. Mice studies showed that the administration of the non-selective inhibitor of cytochrome P450, cimetidine, substantially slowed the rapid in vivo metabolism of 5IA, suggesting that the use of this or similar compounds could reduce the dose of radioactivity needed to successfully image nAChRs in human volunteers. Graphical analysis of PET data from Rhesus monkeys provided binding potential values for 2FA in the thalamus, cortex, striatum and cerebellum that were consistent with the distribution pattern of alpha4beta2* nAChRs. Methodology was developed and data were collected for estimating the density of nAChRs in the thalamus of non-human primates (NHPs). In collaboration with researchers from the University of Michigan, the loss of nAChRs in the striatum of unilaterally MPTP-lesioned NHPs with 2FA and PET was demonstrated. Kinetic studies with 2FA and PET in NHPs revealed that 2FA accumulates relatively slowly in brain, partially because its low lipophilicity slows its blood-brain-barrier penetration. A series of 5-heteryl-6-halogeno-A-85380 derivatives with binding affinity (Ki) at the nicotinic acetylcholine receptor (nAChR) ranging from 3 to 150 pM and a lipophilicity (logD) range of -1.6 to +1.5 has been synthesized as potential PET ligands. Most ligands of the series exhibited a higher binding affinity at the alpha4beta2* subtype of nAChRs than epibatidine. Molecular modeling studies revealed an important role of the orientation of the external heterocyclic ring on the binding affinity of the ligands with nAChRs. Two compounds of the series were radiolabeled with 18F. Recent PET studies with one of these compounds ([18F]NIDA52189) demonstrated that its binding potential values in Rhesus monkey brain was ca. 2.5 times that of 2-[18F]F-A-85380, the only available PET radiotracer for imaging cerebral nAChR in humans. Therefore we conclude that [18F]NIDA52189 and several other members of the series, when radiolabeled, will be suitable for quantitative imaging of extrathalamic nAChRs. Exploration of the central CB1 cannabinoid receptors using PET will allow for an understanding of the pharmacological and physiological role played by these receptors in the CNS. Current tracers are highly lipophilic compounds that exhibit very high nonspecific to specific binding ratios and as a result are inapt for use in humans. We have synthesized a series of less lipophilic analogues of SR141716 to serve as potential radioligands. Some of these compounds possess lower lipophilicity values and comparable binding affinity to SR141716. A facile method for the synthesis of C-4 fluoro analogues of SR141716 has been developed and using a functional electrophysiological assay, we demonstrated that several compounds of the series possess antagonistic properties and are able to rapidly and completely reverse the effects of WIN55,221-2. The methoxy analogue of SR141716 was selected as a potential target for the development of corresponding 11C and H3-labeled derivatives. Greater accumulation of radioactivity after administration of this compound to mice was observed in CB1-rich regions (e.g., hippocampus, striatum and cerebellum) than in receptor poor brain regions, suggesting specific binding to these receptors. Similar findings were obtained in PET studies of Rhesus monkeys. CRH acts as a major regulator of the hypothalamic-pituitary-adrenal (HPA) axis coordinating neuroendocrine, autonomic, immune, and behavioral responses to stress. It is prevalent in the central nervous system (CNS) where it acts as a neurotransmitter. A high-affinity, nonpeptide radioligand for the CRHR1 was synthesized and showed distribution in rat brain consistent with CRHR1 using in vitro autoradiography. This is the first nonpeptide radiotracer combining high affinity and appropriate lipophilicity that penetrates the blood-brain barrier and hence has the potential to be used for PET imaging studies. In vivo visualization of changes in the CRH1 receptor or its occupancy would further the understanding of the role of stress in drug abuse.

宠物区 成像和量化人脑中烟碱受体的能力可能对更好地理解吸烟成瘾的神经生物学至关重要。A-85380和A-84543的类似物已通过正电子发射断层扫描（PET）和单光子发射计算机断层扫描（SPECT）评价为烟碱乙酰胆碱受体（nAChR）的显像剂。动物辐射剂量测定和毒理学研究证明了5-[I-125]碘-A-85380（5IA）的安全性。与耶鲁大学合作，使用5IA的SPECT研究显示，可以在不吸烟的人类志愿者中定量大脑nAChR。同样，在非吸烟者中进行的第一项2-[F-18]fluoro-A-85380（2FA）人体PET研究证明了对丘脑中的nAChR进行定量成像并在含有低至中等受体密度的大脑区域中可视化这些受体的可行性，并且在剂量限度内对单个志愿者进行多项研究是可能的。此外，通过证明对血压和心电图无影响，确定了2FA在人体中的心血管安全性。小鼠研究表明，细胞色素P450的非选择性抑制剂西咪替丁的施用显著减缓了5IA的快速体内代谢，表明使用该化合物或类似化合物可以减少在人类志愿者中成功成像nAChR所需的放射性剂量。恒河猴PET数据的图形分析提供了丘脑、皮质、纹状体和小脑中2FA的结合电位值，这与α 4 β 2 * nAChR的分布模式一致。开发了方法学并收集了用于估计非人灵长类动物（NHP）丘脑中nAChR密度的数据。与密歇根大学的研究人员合作，用2FA和PET证明了单侧MPTP损伤的NHP纹状体中nAChR的损失。NHP中2FA和PET的动力学研究表明，2FA在脑中积累相对缓慢，部分原因是其低亲脂性减缓了其血脑屏障渗透。已合成了一系列5-杂基-6-卤代-A-85380衍生物作为潜在的PET配体，其对烟碱乙酰胆碱受体（nAChR）的结合亲和力（Ki）范围为3至150 pM，亲脂性（logD）范围为-1.6至+1.5。该系列的大多数配体在nAChR的α 4 β 2 * 亚型上表现出比地棘蛙素更高的结合亲和力。分子模拟研究揭示了一个重要的作用的外部杂环的配体与nAChRs的结合亲和力的方向。该系列的两种化合物用18F放射性标记。最近对其中一种化合物（[18 F] NIDA 52189）的PET研究表明，其在恒河猴脑中的结合电位值约为1.25。2.5 2-[18 F]F-A-85380是唯一可用的PET放射性示踪剂，可用于人类大脑nAChR成像。因此，我们得出结论，[18 F] NIDA 52189和该系列的其他几个成员，当放射性标记时，将适用于丘脑外nAChRs的定量成像。 探索中央CB 1大麻素受体使用PET将允许了解这些受体在中枢神经系统中发挥的药理学和生理学作用。目前的示踪剂是高度亲脂性的化合物，其表现出非常高的非特异性与特异性结合比率，因此不适合用于人类。我们合成了一系列亲脂性较低的SR 141716类似物，作为潜在的放射性配体。其中一些化合物具有较低的亲脂性值和与SR 141716相当的结合亲和力。开发了一种合成SR 141716的C-4氟类似物的简便方法，并使用功能性电生理学试验，我们证明了该系列的几种化合物具有拮抗特性，能够快速完全逆转WIN 55，221-2的作用。选择SR 141716的甲氧基类似物作为开发相应11 C和H3标记衍生物的潜在靶点。向小鼠施用该化合物后，在富含CB 1的区域（例如，海马、纹状体和小脑）中的受体比受体贫乏的脑区域中的受体多，表明与这些受体的特异性结合。在恒河猴的PET研究中获得了类似的发现。 CRH作为下丘脑-垂体-肾上腺（HPA）轴的主要调节者，协调神经内分泌、自主神经、免疫和行为对应激的反应。它在中枢神经系统（CNS）中普遍存在，在那里它作为神经递质发挥作用。合成了CRHR 1的高亲和力非肽放射性配体，并使用体外放射自显影术显示其在大鼠脑中的分布与CRHR 1一致。这是第一种结合了高亲和力和适当亲脂性的非肽放射性示踪剂，可穿透血脑屏障，因此有可能用于PET成像研究。CRH 1受体或其占用的变化的体内可视化将进一步了解压力在药物滥用中的作用。