Contribution of simultaneous PET-MRI to understanding the neuropharmacology of 5-HT_1A receptor biased agonists.

Objectives: The recent neuropharmacological concept of “biased agonism” implies the capacity of highly specific agonists to target specific intracellular pathways in specific brain areas. In the context of serotonin pharmacotherapy, 5-HT_1A receptor biased agonists can be of interest to optimize pharmacological treatments of several neuropsychiatric disorders. The aim of this study was to bring additional support to this concept thanks to simultaneous functional MRI and PET molecular imaging (PET-MRI). We compared two biased agonists, F13640 (a drug-candidate for the treatment of L-DOPA-induced dyskinesia) and F15599 (a drug-candidate for the treatment of breathing deficits in Rett syndrome), at different doses, in anaesthetized cats. The drug occupancy was measured by PET imaging with [¹⁸F]MPPF, a 5-HT_1A receptor radiopharmaceutical, after administration of both agonists and was correlated with the consequent brain activation patterns.

Methods: PET and fMRI data were acquired simultaneously using a Siemens Biograph mMR hybrid camera. [¹⁸F]MPPF was injected in a 90-min perfusion (bolus followed by a constant infusion) in isoflurane-anesthetized cats (n=4). After a post-injection equilibrium period of 50 min, F13640 or F15599 was injected i.p. The 5-HT_1A receptor occupancy was quantified by comparing [¹⁸F]MPPF ROI-based and voxel-based values, before and after the pharmacological challenge. Thirty minutes after the beginning of the PET acquisition, continuous T2[asterisk]EPI MRI acquisitions were performed to measure the BOLD signal. The fMRI session was divided into 20 minutes of baseline and 20 minutes after drug injection. A voxel based analysis of the fMRI data was performed at an individual level, followed by a second-level analysis. This PET-MRI protocol was replicated for each cat with increasing concentrations of F13640 and F15599 (0.04 - 0.08 - 0.16 mg/kg ip).

Results: PET and fMRI data, taken together, showed clear differences between the two agonists in terms of binding and subsequent activation patterns. F13640 displayed similar affinities for presynaptic and postsynaptic 5-HT_1A receptors and elicited BOLD modifications in multiple brain regions. In comparison, F15599 showed a preference for postsynaptic receptors, with little capacity to elicit 5-HT_1A activation in the raphe nucleus.

Conclusion: This study is the first simultaneous exploration of a drug 5-HT_1A receptor occupancy and its consequences in terms of brain activation. Simultaneous PET-MRI represents a powerful tool in neuropharmacology and opens new ways to address the innovative concept of biased agonism. Research Support: This work was performed within the framework of the LABEX PRIMES (ANR-11-LABX-0063) of Université de Lyon, within the program "Investissements d'Avenir" (ANR-11-IDEX-0007) operated by the French National Research Agency (ANR). This research was funded by Neurodis Foundation, Lyon, France.