RT Journal Article SR Electronic T1 Development of high potency and highly selective ligands for Sphingosine 1-Phosphate Receptor JF Journal of Nuclear Medicine JO J Nucl Med FD Society of Nuclear Medicine SP 1107 OP 1107 VO 56 IS supplement 3 A1 Rosenberg, Adam A1 Liu, Hui A1 Tu, Zhude YR 2015 UL http://jnm.snmjournals.org/content/56/supplement_3/1107.abstract AB 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