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Binding of the D3-preferring antipsychotic candidate F17464 to dopamine D3 and D2 receptors: a PET study in healthy subjects with [11C]-(+)-PHNO

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Abstract

Rationale

F17464, a dopamine D3 receptor antagonist with relatively high D3 selectivity (70 fold vs D2 in vitro), exhibits an antipsychotic profile in preclinical studies, and therapeutic efficacy was demonstrated in a randomized placebo-controlled clinical trial in patients with schizophrenia (Bitter et al. Neuropsychopharmacology 44(11):1917–1924, 2019).

Objective

This open-label study in healthy male subjects aimed at characterizing F17464 binding to D3/D2 receptors and the time course of receptor occupancy using positron emission tomography (PET) imaging with a D3-preferring tracer, [11C]-(+)-PHNO.

Methods

PET scans were performed at baseline and following a single 30 mg or 15 mg dose of F17464 (3 subjects/dose), and blood samples were collected for pharmacokinetic analysis. Receptor occupancy was calculated based upon reduction in binding potential of the tracer following F17464 administration. The relationship between plasma F17464 concentration and D3/D2 receptor occupancy was modeled and the plasma concentration corresponding to 50% receptor occupancy (EC50) calculated.

Results

Both doses of F17464 robustly blocked [11C]-(+)-PHNO D3 receptor binding, with substantial occupancy from 1 h post-administration, which increased at 6–9 h (89–98% and 79-87% for the 30 mg and 15 mg groups, respectively) and remained detectable at 22 h. In contrast, D2 binding was only modestly blocked at all time points (< 18%).

F17464 exhibited a combination of rapid peripheral kinetics and hysteresis (persistence of binding 22 h post-dose despite low plasma concentration). The best estimate of the EC50 was 19 ng ml−1 (~ 40 nM).

Conclusion

Overall, F17464 was strongly D3-selective in healthy volunteers, a unique profile for an antipsychotic candidate drug.

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Acknowledgments

The authors thank Agata Jurewicz for her aid with quality control of [11C]-(+)-PHNO; Xiaoyan Xu, Rawad Ayoub, Elizabeth Hackett, John Castrillon, and Jiayan Meng for the excellent technical support in the acquisition and analysis of the PET data; Marie-Thérèse Pétrissans, MD, for her participation in the study set-up and clinical monitoring; and Hannah Bartrum, PhD, for her editorial assistance in the preparation of this manuscript.

Funding

Institut de Recherche Pierre Fabre provided funding for the study.

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Correspondence to Mark Slifstein.

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Conflict of interest

The employers of AA-D, MS, RRG, RFS, and TBC received payment from Pierre Fabre for research support/services. AM and MG are employees of Institut de Recherche Pierre Fabre. VB, LL, FT, and PS were employees at the time of their involvement in the study. CD, PC, SJ, and SO declare no conflict of interest.

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Slifstein, M., Abi-Dargham, A., Girgis, R.R. et al. Binding of the D3-preferring antipsychotic candidate F17464 to dopamine D3 and D2 receptors: a PET study in healthy subjects with [11C]-(+)-PHNO. Psychopharmacology 237, 519–527 (2020). https://doi.org/10.1007/s00213-019-05387-w

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