title: 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.
abstract: 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 of11C-JNJ-42491293 were determined in humans. Because of an unexpected high myocardial retention, additional11C-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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Nuclear Medicine, University Hospital Leuven, Leuven, Belgium gil.leurquin-sterk@uzleuven.be.
authors.forename: Gil
authors.initials: G
authors.lastname: Leurquin-Sterk
authors.affiliation: Laboratory for Radiopharmacy, KU Leuven-University of Leuven, Leuven, Belgium.
authors.forename: Sofie
authors.initials: S
authors.lastname: Celen
authors.affiliation: Division of Nuclear Medicine, University Hospital Leuven, Leuven, Belgium.
authors.forename: Koen
authors.initials: K
authors.lastname: Van Laere
authors.affiliation: Division of Nuclear Medicine, University Hospital Leuven, Leuven, Belgium.
authors.forename: Michel
authors.initials: M
authors.lastname: Koole
authors.affiliation: Laboratory for Radiopharmacy, KU Leuven-University of Leuven, Leuven, Belgium.
authors.forename: Guy
authors.initials: G
authors.lastname: Bormans
authors.affiliation: Janssen Research & Development, Janssen Pharmaceutica Nevada, Beerse, Belgium.
authors.forename: Xavier
authors.initials: X
authors.lastname: Langlois
authors.affiliation: Centre for Clinical Pharmacology, University Hospital Leuven, Leuven, Belgium; and.
authors.forename: Anne
authors.initials: A
authors.lastname: Van Hecken
authors.affiliation: Janssen Research & Development, Janssen Pharmaceutica Nevada, Beerse, Belgium.
authors.forename: Paula
authors.initials: P
authors.lastname: Te Riele
authors.affiliation: Janssen Research & Development, Janssen-Cilag SA, Toledo, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Alcázar
authors.affiliation: Centre for Clinical Pharmacology, University Hospital Leuven, Leuven, Belgium; and.
authors.forename: Alfons
authors.initials: A
authors.lastname: Verbruggen
authors.affiliation: Centre for Clinical Pharmacology, University Hospital Leuven, Leuven, Belgium; and.
authors.forename: Jan
authors.initials: J
authors.lastname: de Hoon
authors.affiliation: Janssen Research & Development, Janssen-Cilag SA, Toledo, Spain.
authors.forename: Jose-Ignacio
authors.initials: JI
authors.lastname: Andrés
authors.affiliation: Janssen Research & Development, Janssen Pharmaceutica Nevada, Beerse, Belgium.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Schmidt
mesh_terms: D000328:Adult; D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism*; D002250:Carbon Radioisotopes / Q000493:pharmacokinetics*; D018691:Excitatory Amino Acid Antagonists / Q000493:pharmacokinetics*; D006801:Humans; D007553:Isotope Labeling; D008297:Male; D008657:Metabolic Clearance Rate; D057054:Molecular Imaging / Q000379:methods; D009928:Organ Specificity; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D014018:Tissue Distribution; D055815:Young Adult
chemical_list: D002250:Carbon Radioisotopes; D018691:Excitatory Amino Acid Antagonists; D019275:Radiopharmaceuticals; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2
keywords: PET; knockout models; mGluR2; positive allosteric modulator; specificity