为了能够对周围器官中的血管加压素1A(V1A)受体进行非侵入性实时定量,我们试图开发一种合适的PET探针,该探针可以在体外和体内进行特异性和选择性的V1A受体成像。
我们合成了一种高亲和力和选择性的配体,指定化合物17。目标结构用碳-11标记,并通过细胞摄取研究测试其作为V1A靶向PET示踪剂的效用,放射自显影,体内PET成像和离体生物分布实验。
化合物17(PF-184563)和相应的用于放射性标记的前体以49%(超过7个步骤)和40%(超过8个步骤)的总产率合成,分别。对V1A受体的抑制常数为0.9nM,虽然相对于相关的V1B具有优异的选择性,获得V2和OT受体(IC50>10,000nM)。细胞摄取研究显示相当多的V1A结合,在V1A拮抗剂存在下显著降低。相反,在存在V1B和V2拮抗剂的情况下,没有显著的阻滞作用.啮齿动物的体外放射自显影和PET成像研究表明,特异性示踪剂主要在肝脏中结合。Further,胰腺,通过离体生物分布实验,脾和心脏表现出[11C]17([11C]PF-184563)的特异性结合。
我们开发了第一个V1A靶向PET配体,适用于包括肝脏在内的外周器官的亚型选择性受体成像,心,胰腺和脾脏。我们的发现表明[11C]PF-184563可以是研究V1A受体在肝脏疾病中的作用的有价值的工具。以及心血管疾病。
To enable non-invasive real-time quantification of vasopressin 1A (V1A) receptors in peripheral organs, we sought to develop a suitable PET probe that would allow specific and selective V1A receptor imaging in vitro and in vivo.
We synthesized a high-affinity and -selectivity ligand, designated compound 17. The target structure was labeled with carbon-11 and tested for its utility as a V1A-targeted PET tracer by cell uptake studies,
autoradiography, in vivo PET imaging and ex vivo biodistribution experiments.
Compound 17 (PF-184563) and the respective precursor for radiolabeling were synthesized in an overall yield of 49% (over 7 steps) and 40% (over 8 steps), respectively. An inhibitory constant of 0.9 nM towards the V1A receptors was measured, while excellent selectivity over the related V1B, V2 and OT receptor (IC50 >10,000 nM) were obtained. Cell uptake studies revealed considerable V1A binding, which was significantly reduced in the presence of V1A antagonists. Conversely, there was no significant blockade in the presence of V1B and V2 antagonists. In vitro
autoradiography and PET imaging studies in rodents indicated specific tracer binding mainly in the liver. Further, the pancreas, spleen and the heart exhibited specific binding of [11C]17 ([11C]PF-184563) by ex vivo biodistribution experiments.
We have developed the first V1A-targeted PET ligand that is suitable for subtype-selective receptor imaging in peripheral organs including the liver, heart, pancreas and spleen. Our findings suggest that [11C]PF-184563 can be a valuable tool to study the role of V1A receptors in liver diseases, as well as in cardiovascular pathologies.