RT Journal Article SR Electronic T1 What We Observe In Vivo Is Not Always What We See In Vitro: Development and Validation of 11C-JNJ-42491293, A Novel Radioligand for mGluR2 JF Journal of Nuclear Medicine JO J Nucl Med FD Society of Nuclear Medicine SP 110 OP 116 DO 10.2967/jnumed.116.176628 VO 58 IS 1 A1 Gil Leurquin-Sterk A1 Sofie Celen A1 Koen Van Laere A1 Michel Koole A1 Guy Bormans A1 Xavier Langlois A1 Anne Van Hecken A1 Paula te Riele A1 Jesús Alcázar A1 Alfons Verbruggen A1 Jan de Hoon A1 Jose-Ignacio Andrés A1 Mark E. Schmidt YR 2017 UL http://jnm.snmjournals.org/content/58/1/110.abstract AB 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. 11C-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. Methods: 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. Results: 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 11C-JNJ-42491293 were determined in humans. Because of an unexpected high myocardial retention, additional 11C-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. Conclusion: On the basis of in vivo selectivity issues suggested by human distribution and demonstrated in knockout rat models, 11C-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.