Synthesis and evaluation of highly selective quinazoline-2,4-dione ligands for sphingosine-1-phosphate receptor 2

A series of twenty-nine new quinazoline-2,4-dione compounds were synthesized and their IC₅₀ values for binding toward sphingosine-1-phosphate receptor 2 (S1PR2) were determined using a [³²P]S1P binding assay. Seven compounds 2a, 2g, 2h, 2i, 2j, 2k, and 5h exhibit high S1PR2 binding potencies (IC₅₀ values < 50 nM) and four of these new compounds 2g, 2i, 2j, and 2k have IC₅₀ values (<10 nM) of 6.3, 5.7, 4.8, and 2.6 nM, and are highly selective for S1PR2 over other S1PR subtypes, S1PR1, 3, 4, and 5. Compounds 2a and 2i were chosen for C-11 radiosynthesis through O-[¹¹C]methylation of precursors 13 and 2k with good radiochemical yields (35-40%), high chemical and radiochemical purity (>98%), and high molar activity (153-222 GBq μmol^-1, at the end of bombardment). [¹¹C]2a and [¹¹C]2i were further evaluated by the ex vivo biodistribution study. The results showed that both tracers have low brain uptake, preventing their potential for neuroimaging application. Further explorations of this class of S1PR2 PET tracers in peripheral tissue diseases are underway.