TY - JOUR
T1 - Syntheses and
T2 - In vitro biological evaluation of S1PR1 ligands and PET studies of four F-18 labeled radiotracers in the brain of nonhuman primates
AU - Luo, Zonghua
AU - Han, Junbin
AU - Liu, Hui
AU - Rosenberg, Adam J.
AU - Chen, Delphine L.
AU - Gropler, Robert J.
AU - Perlmutter, Joel S.
AU - Tu, Zhude
N1 - Publisher Copyright:
© 2018 The Royal Society of Chemistry.
PY - 2018
Y1 - 2018
N2 - 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 [ 32 P]S1P competitive binding assays. Compounds 10a, 17a, 17b, and 24 exhibited high S1PR1 binding potencies with IC 50 values ranging from 3.9 to 15.4 nM and also displayed high selectivity for S1PR1 over other S1P receptor subtypes (IC 50 > 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 [ 18 F]10a, [ 18 F]17a, and [ 18 F]17b but not [ 18 F]24 crossed the blood brain barrier and had high initial brain uptake. Further validation of [ 18 F]10a, [ 18 F]17a, and [ 18 F]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.
AB - 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 [ 32 P]S1P competitive binding assays. Compounds 10a, 17a, 17b, and 24 exhibited high S1PR1 binding potencies with IC 50 values ranging from 3.9 to 15.4 nM and also displayed high selectivity for S1PR1 over other S1P receptor subtypes (IC 50 > 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 [ 18 F]10a, [ 18 F]17a, and [ 18 F]17b but not [ 18 F]24 crossed the blood brain barrier and had high initial brain uptake. Further validation of [ 18 F]10a, [ 18 F]17a, and [ 18 F]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.
UR - http://www.scopus.com/inward/record.url?scp=85058180870&partnerID=8YFLogxK
U2 - 10.1039/c8ob02609b
DO - 10.1039/c8ob02609b
M3 - Article
C2 - 30462126
AN - SCOPUS:85058180870
SN - 1477-0520
VL - 16
SP - 9171
EP - 9184
JO - Organic and Biomolecular Chemistry
JF - Organic and Biomolecular Chemistry
IS - 47
ER -