Development Of New Approaches To Neuroimaging with PET a

开发 PET 神经影像新方法

• 批准号: 6987767
• 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/6987767
• 关键词: bioimaging /biomedical imaging; cannabinoid receptor; human subject; laboratory rat; magnetic resonance imaging; method development; neuroimaging; nicotinic receptors; positron emission tomography; protein structure function; radiotracer; receptor expression; single photon emission computed tomography

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). In collaboration with Yale University, the SPECT studies with 5IA revealed that cerebral nAChRs can be quantified in human non-smoking volunteers. Toxicological studies in animals demonstrated the safety of 2-[F-18]fluoro-A-85380 (2FA). The first human PET studies in non-smokers with 2-[F-18]fluoro-A-85380 (2FA) demonstrated the feasibility and safety 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. Preliminary analysis of PET studies in smokers with 2FA demonstrate increased densities of nicotinic receptors in many brain regions compared to the brains of non-smokers. 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. 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-[F-18]F-A-85380, the only available PET radiotracer for imaging cerebral nAChR in humans. Preliminary toxicology and dosimetry studies suggest that [F-18]NIDA52189 is suitable for quantitative imaging of extrathalamic nAChRs. Imaging of the central CB1 cannabinoid receptors by PET will improve our understanding of the roles of these receptors in the brain. Existing PET radiotracers for imaging CB1 are very lipophilic compounds with high non-specific to specific binding ratios and as a result are not adequate for quantitative studies. A 14 member series of analogs of 1-[(N-methyl-piperidin-2-yl)methyl]-3-naphthoylindole, a CB1 agonist with high binding affinity, with reduced lipophilicities has been synthesized. The lead compound shows a Ki of 0.9 nM, which represents one of the highest affinities observed for CB1 receptor ligands; further, it has a cLogD value, which should reduce non specific binding, a problem observed with all previously tested ligands. Our study showed that substitutions to the lead compound at the 4 position on the naphthyl ring gave similar Ki values that allowed us to vary the lipophilicity of the ligand, giving cLogD values in the range of 2.7 to 4.5. Substituting a fluorine atom for hydrogen gave a derivative with the lowest Ki value, 0.7 nM, and an unexpectedly low experimental LogD of 2.6. A 4-nitro precursor for nucleophic radio-fluorination of this compound has been used giving good radiochemiccal yields and specific activity. When the entomerically purified tracer was used in an ex-vivo study on mice the target to non-target ratios were about 1.7-1.8. for measurements from the hippocampus to brain stem regions. Other tracers are planned including the 4-(2-hydroxyethyl)naphthoyl derivative which has a better combination of lipophilicity and binding. Corticotropin-Releasing Hormone (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 receptor subtype 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.

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。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。动物毒理学研究证明了2-[F-18]氟-A-85380（2FA）的安全性。在非吸烟者中使用2-[F-18]fluoro-A-85380（2FA）进行的第一项人体PET研究证明了在丘脑中定量成像nAChR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和安全性，并且在剂量限度内对单个志愿者进行多项研究是可能的。对使用2FA的吸烟者的PET研究的初步分析表明，与非吸烟者的大脑相比，许多大脑区域中的烟碱受体密度增加。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。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-[F-18]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。初步毒理学和剂量学研究表明，[F-18] NIDA 52189适用于丘脑外nAChRs的定量成像。 通过PET对中央CB 1大麻素受体进行成像将提高我们对这些受体在大脑中作用的理解。现有的用于成像CB 1的PET放射性示踪剂是非常亲脂的化合物，具有高的非特异性与特异性结合比率，因此不足以进行定量研究。合成了一系列1-[（N-甲基-哌啶-2-基）甲基]-3-萘甲酰基吲哚（CB 1激动剂）的14个成员的类似物，其具有高结合亲和力，具有降低的亲脂性。先导化合物显示Ki为0.9 nM，这代表了对CB 1受体配体观察到的最高亲和力之一;此外，它具有cLogD值，这应该减少非特异性结合，这是所有先前测试的配体观察到的问题。我们的研究表明，在萘基环上的4位取代先导化合物得到类似的Ki值，这使我们能够改变配体的亲脂性，使cLogD值在2.7至4.5的范围内。用氟原子取代氢原子得到的衍生物Ki值最低，为0.7 nM，实验LogD出乎意料地低，为2.6。用4-硝基前体作该化合物的亲核放射性前体，得到了良好的放化产率和比活性。当在小鼠的离体研究中使用内聚体纯化的示踪剂时，靶与非靶的比率为约1.7-1.8。从海马体到脑干区域的测量。计划使用其他示踪剂，包括4-（2-羟乙基）萘甲酰基衍生物，其具有更好的亲脂性和结合力。 促肾上腺皮质激素释放激素（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受体亚型一致。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。