Development of PET radioligands for cerebral cannabinoid receptor (CB1)

描述（由申请人提供）：该提案的总体目标是开发用于人类受试者脑大麻素受体（CB1）的定量正电子发射断层扫描（PET）成像的放射配体。目前迫切需要CB1的PET成像来研究大麻素系统在精神分裂症、抑郁症、肥胖、药物依赖等许多疾病中的作用。目前，只有一种放射性配体可用于此目的，其成像性能较差。R21：最近[11C]JHU75528是我们课程组开发的首个具有合理的动物CB1受体定量PET成像性能的放射配体。由于缺乏CB1受体的PET成像数据和很少的跨物种信息，尚不清楚[11C]JHU75528是否能令人满意地用于人类。在前期研究过程中，我们合成了三种新的JHU75528类似物，它们的体外特性（结合亲和力和亲脂性）都优于JHU75528。在R21阶段，这些CB1配体将用PET同位素进行放射性标记，并在狒狒中测试其PET成像特性。将三种新型放射性配体与先前研究的[11C]JHU75528进行狒狒PET成像特性比较。在此基础上，选择在CB1受体密度高、其他影像学特性好的狒狒脑区，脑摄取最好、结合电位（BP>1.3-1.5）值最大的两个放射配体进行R33期。R33：在项目的R33阶段，两种候选放射性配体将被量化为药物代动力学、分布密度、结合电位和CB1受体在狒狒大脑中的占用。两种候选放射性配体在啮齿动物中的辐射剂量学和毒理学实验将与狒狒的PET扫描同时进行，并将允许为这两种放射性配体提交医生赞助的探索性IND （eIND）。在eIND获得FDA批准后，将对两种放射性配体进行人体放射性示踪剂选择PET成像研究，以选择一种结合电位最高（BP bbb1）且在人脑中摄取最多的放射性配体。人体辐射剂量测定将获得最佳的放射配体。人体辐射剂量学数据将确保放射性配体在每个受试者两次或更多次PET扫描中的辐射安全性，并允许进行人体测试/重新测试PET扫描和剂量依赖的利莫那班（一种选择性CB1拮抗剂和一种新兴的抗肥胖药物）的占用。预计临床有效剂量的利莫那班的占有率将超过30%。这将证明最佳开发的放射配体在人体中的体内饱和性，并说明其作为CB1显像剂和CB1治疗药物未来开发中的生物标志物的用途。开发用于大麻素受体1型（CB1）正电子发射断层扫描（PET）成像的放射配体，对于研究大麻素系统在神经精神疾病、肥胖、药物依赖和各种其他疾病中的作用以及开发大麻素能药物治疗这些疾病具有重要意义。

DESCRIPTION (provided by applicant): The overall objective of the proposal is to develop a radioligand for quantitative positron emission tomography (PET) imaging of the cerebral cannabinoid receptor (CB1) in human subjects. There is an urgent need for PET imaging of the CB1 to study the role of the cannabinoid system in schizophrenia, depression, obesity, drug dependence and many other disorders. Currently, only one radioligand is available for this purpose and its properties for imaging are poor. R21: Recently [11C]JHU75528, the first radioligand with reasonable properties for quantitative PET imaging of the CB1 receptor in animals, was developed by our group. Because of the lack of available data on PET imaging of the CB1 receptor and little cross-species information, it is not clear if [11C]JHU75528 will be satisfactory for use in humans. In the course of our Preliminary Studies, we synthesized three novel analogs of JHU75528 with in vitro properties (binding affinity and lipophilicity) superior to JHU75528. In the R21 phase these CB1 ligands will be radiolabeled with PET isotopes and tested for their PET imaging properties in baboon. The baboon PET imaging properties of three novel radioligands and the previously studied [11C]JHU75528 will be compared. Based on this comparison, the two radioligands with the best brain uptake, greatest values of binding potential (BP>1.3-1.5) in the baboon brain regions with high density of CB1 receptors and good other imaging properties will be selected for the R33 phase. R33: In the R33 phase of the project both candidate radioligands will be quantified for pharmacokinetics, distribution density, binding potential, and occupancy of the CB1 receptor in the baboon brain. Radiation dosimetry and toxicology experiments in rodents for both candidate radioligands will be conducted simultaneously with the baboon PET scans and will allow filing a physician-sponsored Exploratory IND (eIND) for these two radioligands. After the eIND approval by the FDA, the human radiotracer selection PET imaging studies with two radioligands will be performed to select the one radioligand with the highest binding potential (BP>1) and uptake in the human brain. Human radiation dosimetry will be obtained for the best radioligand. The radiation dosimetry data in humans will assure the radiation safety of the radioligand in two or more PET scans per human subject and allow carrying out human test/re-test PET scans and dose dependent occupancy of Rimonabant, a selective CB1 antagonist and an emerging anti-obesity drug. It is anticipated that clinically effective doses of Rimonabant will yield occupancy in excess of 30%. This will demonstrate in vivo saturability of the best developed here radioligand in humans and also illustrate its use as an imaging agent for the CB1 and as a biomarker in the future development of therapeutic CB1 drugs. Development of radioligands for positron emission tomography (PET) imaging of the cannabinoid receptors type 1 (CB1) is of great importance for studying the role of the cannabinoid system in neuropsychiatric disorders, obesity, drug dependence and a variety of other disorders as well as for developing cannabinergic medications to treat these conditions.