E. Hoeben (1), A. Brochot (1), V. Sinha (2), P. de Boer (3), K. Wuyts (4), H. Bohets (5), E. Scheers (5), X. Langlois (6), P. Te Riele (6), and H. Lavreysen (6)
Janssen Research & Development, a Division of Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340 Beerse Belgium
Objectives: JNJ-mGluR2 PAM, a positive allosteric modulator of the metabotropic glutamate receptor-2 and 5-HT2AR antagonist, is currently in development for the treatment of disorders of the central nervous system [1,2]. To understand the pharmacological profile of JNJ-mGluR2 PAM and to define exposure vs. 5-HT2AR occupancy relationship in man, a PET study was performed in healthy male subjects [3]. To help in designing a PET study, 5-HT2AR occupancies in man were predicted based on in vitro and in vivo nonclinical pharmacology data in the rat.
Methods: In vitro functional and radioligand binding experiments were performed to investigate the in vitro activity and binding of JNJ-mGluR2 PAM and its major metabolite (M47) to human 5-HT2AR. Receptor occupancy assays were conducted in rats to evaluate JNJ-mGluR2 PAM occupancy to 5-HT2AR in vivo. Plasma concentrations vs. 5-HT2AR modeling was performed in rat and used to predict the 5-HT2AR occupancy in man. The relationship between predicted 5-HT2AR occupancy and simulated plasma concentrations in man was used to predict 5-HT2AR occupancy in man at clinical doses of 50 to 700 mg.
Results: In vitro preclinical experiments showed that JNJ-mGluR2 PAM is a weak 5-HT2AR antagonist. In rats, JNJ-mGluR2 PAM is rapidly metabolized to M47 which is a relatively potent and selective 5-HT2AR antagonist. Modeling experiments suggested that M47 significantly contributes to the 5-HT2AR binding in the rat but in humans only limited metabolism to M47 has been observed. Accounting for the different contributions of parent and metabolite and the differences in free fraction in rat vs. man, 5-HT2AR occupancy could be predicted in man based on exposure vs. 5-HT2AR modeling in the rat. At clinical doses of 50 to 700 mg, predicted 5-HT2AR occupancy in man ranged between 5% and 25%. The human PET data confirmed minimal 5-HT2AR occupancy by JNJ-mGluR2 PAM in man, which is not expected to be clinically relevant.
Conclusions: 5-HT2AR occupancy could be predicted in man based on nonclinical pharmacology data in the rat, taking into account the difference in free fraction and the different contributions of parent and metabolite in rat vs. man. At clinical doses, predicted 5-HT2AR occupancy in man was low and in good agreement with observed 5-HT2AR occupancy in man. This modeling work illustrated the "translatability" of in vitro and in vivo preclinical information to 5-HT2AR occupancy in man.
References:
[1] Swanson CJ, Bures M, Johnson MP, Linden AM, Monn JA, Schoepp DD. Metabotropic glutamate receptors as novel targets for anxiety and stress disorders. Nat. Rev. Drug. Discov. 2005; 4:131-144.
[2] Patil ST, Zhang L, Martenyi F, Lowe SL, Jackson KA, Andreev BV, et al. Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized Phase 2 clinical trial. Nat. Med. 2007; 13:1102-1107.
[3] Ito H, Nyberg S, Halldin C, Lundkvist C, Farde L. PET imaging of central 5-HT2A receptors with carbon-11-MDL 100,907. J. Nucl. Med. 1998; 39(1):208-214.
Reference: PAGE 22 (2013) Abstr 2771 [www.page-meeting.org/?abstract=2771]
Poster: CNS