Abstract
1107
Objectives Sphingosine 1-phosphate receptor 1 (S1PR1) is highly expressed in inflamed tissues, such as multiple sclerosis lesions. A ligand possessing high potency and selectivity for S1PR1 and containing fluorine will have the potential to be radiolabeled with fluorine-18. An 18F labeled S1PR1 radioligand will be very useful for investigating the expression change of S1PR1 in vivo for inflammation relative diseases in animals.
Methods 11 novel selective S1PR1 ligands that containing a fluorine atom were synthesized in a four step sequence and characterized. The ligands were optimized for S1PR1 potency, as well as selective binding to S1PR1 over S1PR2/3. Binding affinities were determined by competing against the binding of [32P]S1P to S1PRs.
Results Structure activity relationship studies indicated that ligands containing an oxadiazole core were superior to those containing a benzoxazole core. Additionally the presence of an amino acid head group was beneficial for potency. Exploration of the non-polar tail group showed a narrow tolerance for derivatization. Using the in vitro radioligand binding assay five compounds showed <100 nM IC50, while two compounds demonstrated <10 nM binding affinities.
Conclusions 11 new S1PR1 selective compounds were prepared. Two compounds are highly active and selective. The lead compounds have excellent potency for S1PR1 (IC50 = 2.63 nM & 8.53 nM), excellent selectivity over S1PR2/3 (>1000 nM); they will be radiolabeled for performing in vivo evaluation in animal models of inflammation.
Research Support DESC0008432