Leurquin-Sterk Gil, Celen Sofie, Van Laere Koen, Koole Michel, Bormans Guy, Langlois Xavier, Van Hecken Anne, Te Riele Paula, Alcázar Jesús, Verbruggen Alfons, de Hoon Jan, Andrés Jose-Ignacio, Schmidt Mark E
Division of Nuclear Medicine, University Hospital Leuven, Leuven, Belgium
Laboratory for Radiopharmacy, KU Leuven-University of Leuven, Leuven, Belgium.
J Nucl Med. 2017 Jan;58(1):110-116. doi: 10.2967/jnumed.116.176628. Epub 2016 Jul 28.
Positive allosteric modulators (PAM) of metabotropic glutamate receptor 2 (mGluR2) are a potential therapy for anxiety, schizophrenia, and addiction. Aside from pathophysiologic imaging studies, an mGluR2 PET tracer would enable confirmation of sufficient central target engagement and assist dose selection for proof-of-concept studies of PAM compounds. C-JNJ-42491293, a novel high-affinity radioligand (human 50% inhibitory concentration = 9.6 nM) for the PAM site of mGluR2, was evaluated as a selective mGluR2 PAM PET tracer.
In vitro and ex vivo autoradiography binding experiments in Wistar and in mGluR2 knockout and wildtype rats as well as in vivo biodistribution and brain PET imaging studies in wildtype and mGluR2 knockout rats in a primate and in humans were performed.
In vitro binding studies and in vivo imaging studies in Wistar rats showed moderate brain uptake, with a distribution pattern fully consistent with the reported intracerebral distribution of mGluR2. Given these promising findings, biodistribution, dosimetry, and brain kinetic modeling of C-JNJ-42491293 were determined in humans. Because of an unexpected high myocardial retention, additional C-JNJ-42491293 imaging studies were performed in recently available mGluR2 knockout and wildtype rats and in a monkey using a structurally distinct mGluR2 PAM ligand with affinity for the same site, demonstrating off-target binding in vivo that could not have been anticipated from previous in vitro experiments. To date, the target of this non-mGluR2 tracer binding remains unknown.
On the basis of in vivo selectivity issues suggested by human distribution and demonstrated in knockout rat models, C-JNJ-42491293 was considered unsuitable as a specific PET ligand for in vivo imaging of mGluR2. These results emphasize the importance of elaborated in vitro/in vivo comparative studies and, when available, validation with knockout animal models or structurally distinct ligands with affinity for the same site, in radiotracer development.
代谢型谷氨酸受体2（mGluR2）的正变构调节剂（PAM）是治疗焦虑症、精神分裂症和成瘾的一种潜在疗法。除了病理生理学成像研究外，一种mGluR2正电子发射断层扫描（PET）示踪剂将能够确认足够的中枢靶点结合，并有助于为PAM化合物的概念验证研究选择剂量。C-JNJ-42491293是一种针对mGluR2的PAM位点的新型高亲和力放射性配体（人50%抑制浓度=9.6 nM），被评估为一种选择性mGluR2 PAM PET示踪剂。
在Wistar大鼠、mGluR2基因敲除和野生型大鼠中进行体外和离体放射自显影结合实验，并在灵长类动物和人类的野生型和mGluR2基因敲除大鼠中进行体内生物分布和脑PET成像研究。
Wistar大鼠的体外结合研究和体内成像研究显示脑摄取适中，其分布模式与报道的mGluR2脑内分布完全一致。鉴于这些有前景的发现，在人体中确定了C-JNJ-42491293的生物分布、剂量测定和脑动力学模型。由于意外的高心肌滞留，使用对同一位点具有亲和力的结构不同的mGluR2 PAM配体，在最近获得的mGluR2基因敲除和野生型大鼠以及一只猴子中进行了额外的C-JNJ-42491293成像研究，证明了体内存在非靶点结合，这是之前的体外实验无法预测到的。迄今为止，这种非mGluR2示踪剂结合的靶点仍然未知。
基于人体分布所提示并在基因敲除大鼠模型中得到证实的体内选择性问题, C-JNJ-42491293被认为不适宜作为mGluR2体内成像的特异性PET配体。这些结果强调了在放射性示踪剂开发中进行详细的体外/体内比较研究以及在有条件时用基因敲除动物模型或对同一位点具有亲和力的结构不同的配体进行验证的重要性。
