1-Arylimidazo[1,5a]chinoxalines as lead compounds for a PDE10A PET tracer

Aim: Phosphodiesterase 10A (PDE10A) plays a key role in cellular signaling by inactivation of the second messengers cAMP and cGMP. The abundant expression of PDE10A in the striatum makes this enzyme a prime target in the therapy of diseases related to this brain area, e.g. schizophrenia and movement disorders. Imaging by PET would allow to investigate the pathomechanism of such diseases and the relation to PDE10A and its expression. Therefore our aim is to develop a PET tracer for PDE10A. Recently 1-arylimidazo[1,5a]quinoxalines have been reported as very potent and selective PDE10A inhibitors.[1] This structural motif was selected as lead structure for the development of a new PET tracer.
Methods: To enable an easy incorporation of F-18 fluoride the 2-fluoropyridine moiety was chosen as fluorine containing building block. For synthesis of the reference compounds different 2-fluoropyridine boronic acids were linked to the tricyclic key intermediate by a palladium catalyzed Suzuki coupling. Characterization of these compounds was done by NMR, HRMS and HPLC. The inhibitory potency of these new fluorinated derivatives was tested in an enzyme assay towards PDE10A and further PDEs. For one candidate which was selected to be labeled with F-18 a precursor was synthesized likewise by a Suzuki coupling with 2-bromopyridine boronic acid. Different reaction conditions were tested for the one step F-18 fluoro-for-bromo substitution.
Results: A small library of reference compounds was synthesized. All compounds possess a high affinity for PDE10A (IC50 < 10 nM) with good to moderate selectivity versus other PDEs. The most selective inhibitor (IC50 = 2.91 nM) was chosen to be further developed as PET tracer. The logD7.4 value of the inhibitor (2.41 ± 0.33) was estimated by HPLC. When the precursor was reacted with F-18 fluoride in DMSO at 140°C under standard conditions (K2CO3, K222) radiolabeling efficiency of 30-50% was obtained within 10 min. At longer reaction times the labeling efficiencies decreased. A purification process including semi-preparative HPLC was established to isolate the radiotracer.
Conclusion: A new fluorinated, potent and selective PDE10A inhibitor was identified. The bromo precursor proved to be a suitable precursor for the F-18 labeling. Good conditions for the nucleophilic aromatic bromo-to-fluoro exchange were found. Further investigations of the tracer including small animal PET studies are currently underway.
Reference: [1] Malamas et. al. J. Med. Chem. 2011,54, 7621-7638.