Development of high potency and highly selective ligands for Sphingosine 1-Phosphate Receptor

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