Syntheses and in vitro biological evaluation of S1PR1 ligands and PET studies of four F-18 labeled radiotracers in the brain of nonhuman primates

Abstract

A series of seventeen hydroxyl-containing sphingosine 1-phosphate receptor 1 (S1PR1) ligands were designed and synthesized. Their in vitro binding potencies were determined using [³²P]S1P competitive binding assays. Compounds 10a, 17a, 17b, and 24 exhibited high S1PR1 binding potencies with IC₅₀ values ranging from 3.9 to 15.4 nM and also displayed high selectivity for S1PR1 over other S1P receptor subtypes (IC₅₀ > 1000 nM for S1PR2–5). The most potent compounds 10a, 17a, 17b, and 24 were subsequently radiolabeled with F-18 in high yields and purities. MicroPET studies in cynomolgus macaque showed that [¹⁸F]10a, [¹⁸F]17a, and [¹⁸F]17b but not [¹⁸F]24 crossed the blood brain barrier and had high initial brain uptake. Further validation of [¹⁸F]10a, [¹⁸F]17a, and [¹⁸F]17b in preclinical models of neuroinflammation is warranted to identify a suitable PET radioligand to quantify S1PR1 expression in vivo as a metric of an inflammatory response.