Neurobiology Research Unit and Center for Integrated Molecular Imaging, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
J Labelled Comp Radiopharm. 2020 Feb;63(2):46-55. doi: 10.1002/jlcr.3808. Epub 2020 Jan 6.
The serotonin 7 (5-HT ) receptor is suggested to be involved in a broad variety of CNS disorders, but very few in vivo tools exist to study this important target. Molecular imaging with positron emission tomography (PET) would enable an in vivo characterization of the 5-HT receptor. However, no clinical PET radiotracer exists for this receptor, and thus we aimed to develop such a tracer. In this study, we present the preclinical evaluation of [ C]Cimbi-701. Cimbi-701 was synthesized in a one-step procedure starting from SB-269970. Its selectivity profile was determined using an academic screening platform (NIMH Psychoactive Drug Screening Program). Successful radiolabeling of [ C]Cimbi-701 and subsequent in vivo evaluation was conducted in rats, pigs and baboon. In vivo specificity was investigated by 5-HT and σ receptor blocking studies. P-gp efflux transporter dependency was investigated using elacridar. [ C]Cimbi-701 could successfully be synthesized. Selectivity profiling revealed high affinity for the 5-HT (K = 18 nM), σ-1 (K = 9.2 nM) and σ-2 (K = 1.6 nM) receptors. In rats, [ C]Cimbi-701 acted as a strong P-gp substrate. After P-gp inhibition, rat brain uptake could specifically be blocked by 5-HT and σ receptor ligands. In pig, high brain uptake and specific 5-HT and σ-receptor binding was found for [ C]Cimbi-701 without P-gp inhibition. Finally, low brain uptake was found in baboons. Both the specific σ-receptor binding and the low brain uptake of [ C]Cimbi-701 displayed in baboon discouraged further translation to humans. Instead, we suggest exploration of this structural class as results indicate that selective 5-HT receptor imaging might be possible when more selective non-P-gp substrates are identified.
血清素 7（5-HT）受体被认为与广泛的中枢神经系统疾病有关，但目前用于研究这一重要靶点的体内工具非常少。正电子发射断层扫描（PET）的分子成像将使 5-HT 受体的体内特征得以实现。然而，目前还没有用于该受体的临床 PET 示踪剂，因此我们旨在开发这样一种示踪剂。在这项研究中，我们介绍了 [C]Cimbi-701 的临床前评估。Cimbi-701 是从 SB-269970 一步法合成的。使用学术筛选平台（NIMH 精神药物筛选计划）确定了其选择性特征。[C]Cimbi-701 的成功放射性标记及其随后的体内评估在大鼠、猪和狒狒中进行。通过 5-HT 和 σ 受体阻断研究研究了体内特异性。使用 elacridar 研究了 P-糖蛋白外排转运蛋白的依赖性。[C]Cimbi-701 可以成功合成。选择性分析显示对 5-HT（K = 18 nM）、σ-1（K = 9.2 nM）和 σ-2（K = 1.6 nM）受体具有高亲和力。在大鼠中，[C]Cimbi-701 是一种强 P-糖蛋白底物。在 P-糖蛋白抑制后，5-HT 和 σ 受体配体可以特异性阻断大鼠脑摄取。在猪中，发现[C]Cimbi-701 未经 P-糖蛋白抑制即可具有高脑摄取和特异性 5-HT 和 σ 受体结合。最后，在狒狒中发现脑摄取较低。[C]Cimbi-701 的特异性 σ 受体结合和低脑摄取均在狒狒中发现，这阻止了其进一步向人类转化。相反，我们建议探索这一结构类别，因为结果表明，当确定出更具选择性的非 P-糖蛋白底物时，可能可以进行选择性 5-HT 受体成像。
