Development of PET radioligands for cerebral cannabinoid receptor (CB1)

描述（由申请方提供）：该提案的总体目标是开发一种放射性配体，用于人类受试者大脑大麻素受体（CB 1）的定量正电子发射断层扫描（PET）成像。迫切需要CB 1的PET成像来研究大麻素系统在精神分裂症，抑郁症，肥胖症，药物依赖和许多其他疾病中的作用。目前，只有一种放射性配体可用于此目的，其成像性能差。R21：最近[11 C] JHU 75528是我们小组开发的第一个具有合理性质的放射性配体，用于动物CB 1受体的定量PET成像。由于缺乏CB 1受体PET成像的可用数据和很少的跨物种信息，尚不清楚[11 C] JHU 75528是否能令人满意地用于人体。在我们的初步研究过程中，我们合成了三种新的JHU 75528类似物，其体外性质（结合亲和力和亲脂性）上级于JHU 75528。在R21阶段，这些CB 1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。将比较三种新型放射性配体和先前研究的[11 C] JHU 75528的狒狒PET成像特性。基于该比较，将选择在具有高密度CB 1受体的狒狒脑区域中具有最佳脑摄取、最大结合电位值（BP>1.3-1.5）和良好其他成像性质的两种放射性配体用于R33期。R33：在该项目的R33阶段，将对两种候选放射性配体的药代动力学、分布密度、结合潜力和狒狒脑中CB 1受体的占有率进行定量。两种候选放射性配体的啮齿动物辐射剂量测定和毒理学实验将与狒狒PET扫描同时进行，并将允许为这两种放射性配体提交医生申办的探索性IND（eIND）。在FDA批准eIND后，将使用两种放射性配体进行人体放射性示踪剂选择PET成像研究，以选择在人脑中具有最高结合潜力（BP>1）和摄取的一种放射性配体。将获得最佳放射性配体的人体辐射剂量。人体中的辐射剂量测定数据将确保放射性配体在每个人类受试者的两次或更多次PET扫描中的辐射安全性，并允许进行人体测试/重新测试PET扫描和利莫那班（一种选择性CB 1拮抗剂和一种新兴的抗肥胖药物）的剂量依赖性占用。预计临床有效剂量的利莫那班将产生超过30%的占用率。这将证明在人体内最好的开发的放射性配体的体内饱和性，并说明其作为CB 1的成像剂和作为生物标志物在未来开发的治疗性CB 1药物。开发用于大麻素受体1型（CB 1）的正电子发射断层扫描（PET）成像的放射性配体对于研究大麻素系统在神经精神障碍、肥胖症、药物依赖和各种其他疾病中的作用以及开发治疗这些疾病的大麻能药物具有重要意义。

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.