Development Of New Pet And Spect Radiotracers

新型宠物和光谱放射性示踪剂的开发

• 批准号: 6535530
• 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/6535530
• 关键词: analog; cannabinoid receptor; cannabinoids; clinical research; drug design /synthesis /production; human subject; nicotine; nicotinic receptors; positron emission tomography; radiotracer; single photon emission computed tomography

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). Based on radiation dosimetry and toxicological studies in animals that demonstrated the safety of 5-[I-125]iodo-A-85380 (5IA) and 2-fluoro-A-85380 (2FA) for use in humans, INDs allowing the administration of these radioligands to humans were submitted. In collaboration with Yale University, the first human studies with 5IA and SPECT were performed and confirmed the safety of doses sufficient to visualize alpha4beta2 nAChRs in the human brain. 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. Methodology was developed and data were collected in kinetic studies of the thalamus in non-human primates (NHPs) for estimating the densities of nAChRs and, in collaboration with researchers from the University of Michigan, visualizing the loss of these receptors in the striatum of unilaterally MPTP-lesioned NHPs with 2FA and PET. 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. Therefore, to collect sufficient data to quantify receptor binding with PET after the bolus administration of 2FA, up to 4 - 6 hours of scanning are required. Such prolonged scanning could limit the practical use of 2FA in human studies, especially due to the 1.8 h half-life of [F-18]. Efforts were directed at developing radioligands with faster kinetics for imaging nAChRs in vivo. To that end, six novel analogs of A-85380 and A-84543 with calculated log P (Clog P) values in the range of 1.2 to 3 were synthesized, radiolabeled and evaluated in vitro and in vivo. Molecular modeling of the structures of these compounds revealed differences in their conformational profiles and the electronic properties, providing insight into structure-activity relationships with nAChRs. The molecular modeling was performed in collaboration with staff in the Medicinal Chemistry Section of the Medications Discovery Research Branch. Increasing the lipophilicity from Clog P = 0.6 (2FA) yielded ligands with faster blood brain barrier penetration and increased nonspecific binding. Although [11C]methyl-PVC, the best radioligand from the series, exhibits specific in vivo receptor binding that is half that of 2FA, [11C]methyl-PVC may be useful for studying the in vivo occupancy of nAChRs by endogenous or exogenous ligands. From in vitro and in vivo studies with these radioligands (Kd values at 37 degrees C: 9 to 600 pM, Clog P values: 0.6 to 3), an algorithm was developed for predicting binding potential (BP). BP is the one of the most important characteristic of a radioligand as it characterizes the specificity of radioligand receptor binding and reflects its suitability for qualitive and quantitative in vivo imaging. BP values for six radioligands calculated from their Kds at 37 oC, their Clog Ps, and the density of alpha4beta2 nAChRs in each brain region of interest and this algorithm were in good agreement with those observed in in vivo in Rhesus monkeys, suggesting that this algorithm might be useful for screening potential compounds for a new radioligand for alpha4beta2 nAChRs with improved characteristics. As part of a new effort to develop radioligands for in vivo imaging of cannabinoid receptors, we synthesized and evaluated in vitro twelve new analogs of SR141716, a selective ligand for CB1 subtype of cannabinoid receptors. Two of these compounds are potentially suitable for use as in vivo imaging agents. Three additional compounds in this series reversed the inhibition of excitatory transmission produced by WIN 55,212-2, a cannabinoid receptor agonist, suggesting that they may be of interest for the treatment of marijuana and cocaine addictions. This work was performed in collaboration with staff in the Cellular Neurophysiology Section of the Cellular Neurobiology Research Branch.

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。基于动物辐射剂量测定和毒理学研究，证明了5-[I-125]碘-A-85380（5IA）和2-氟-A-85380（2FA）用于人体的安全性，提交了允许将这些放射性配体用于人体的IND。与耶鲁大学合作，进行了第一次5IA和SPECT人体研究，并证实了足以使人脑中的α 4 β 2 nAChR可视化的剂量的安全性。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。 开发了方法学，并在非人灵长类动物（NHP）的丘脑动力学研究中收集数据，以估计nAChR的密度，并与密歇根大学的研究人员合作，用2FA和PET可视化单侧MPTP损伤的NHP纹状体中这些受体的损失。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。因此，为了收集足够的数据来量化2FA推注给药后与PET的受体结合，需要长达4 - 6小时的扫描。这种长时间的扫描可能会限制2FA在人体研究中的实际应用，特别是由于[F-18]的半衰期为1.8小时。致力于开发具有更快动力学的放射性配体用于体内nAChR成像。为此，合成了六种新的A-85380和A-84543类似物，其计算log P（Clog P）值在1.2至3的范围内，进行了放射性标记，并在体外和体内进行了评价。这些化合物的结构的分子建模揭示了它们的构象分布和电子性质的差异，提供了深入了解与nAChRs的结构-活性关系。与药物发现研究分支药物化学部门的工作人员合作进行分子建模。从Clog P = 0.6（2FA）增加亲脂性产生具有更快血脑屏障穿透和增加非特异性结合的配体。虽然[11 C]甲基-PVC，从该系列中最好的放射性配体，表现出特异性的体内受体结合，是2FA的一半，[11 C]甲基-PVC可能是有用的研究在体内占用的内源性或外源性配体的nAChR。根据这些放射性配体的体外和体内研究（37 ℃下的Kd值：9至600 pM，Clog P值：0.6至3），开发了用于预测结合潜力（BP）的算法。BP是放射性配体最重要的特征之一，因为它表征了放射性配体受体结合的特异性，并反映了其对定性和定量体内成像的适用性。根据其在37 oC下的Kd、其Clog Ps和每个感兴趣的脑区域中的α 4 β 2 nAChR的密度计算的六种放射性配体的BP值和该算法与在恒河猴体内观察到的BP值非常一致，表明该算法可能用于筛选具有改进特征的α 4 β 2 nAChR的新放射性配体的潜在化合物。 作为开发用于大麻素受体体内成像的放射性配体的新努力的一部分，我们合成并在体外评估了12种SR 141716的新类似物，SR 141716是大麻素受体CB 1亚型的选择性配体。这些化合物中的两种可能适合用作体内成像剂。该系列中的另外三种化合物逆转了大麻素受体激动剂WIN 55，212 -2产生的兴奋性传递抑制，表明它们可能对大麻和可卡因成瘾的治疗有意义。这项工作是与细胞神经生物学研究分支的细胞神经生理学部分的工作人员合作进行的。