TY - JOUR
T1 - Syntheses and in vitro evaluation of new S1PR1 compounds and initial evaluation of a lead F-18 radiotracer in rodents
AU - Luo, Zonghua
AU - Rosenberg, Adam J.
AU - Liu, Hui
AU - Han, Junbin
AU - Tu, Zhude
N1 - Publisher Copyright:
© 2018 Elsevier Masson SAS
PY - 2018/4/25
Y1 - 2018/4/25
N2 - Thirteen new sphingosine-1-phosphate receptor 1 (S1PR1) ligands were designed and synthesized by replacing azetidine-3-carboxylic acid moiety of compound 4 with new polar groups. The in vitro binding potency of these new analogs toward S1PR1 was determined. Out of 13 new compounds, four compounds 9a, 10c, 12b, and 16b displayed high S1PR1 binding potency with IC50 values of 13.2 ± 3.2, 14.7 ± 1.7, 9.7 ± 1.6, and 6.3 ± 1.3 nM, respectively; further binding studies of these four ligands toward S1PR2-5 suggested they are highly selective for S1PR1 over other S1PRs. The radiosynthesis of the lead radiotracer [18F]12b was achieved with good radiochemical yield (∼14.1%), high radiochemical purity (>98%), and good specific activity (∼54.1 GBq/μmol, decay corrected to the end of synthesis, EOS). Ex vivo autoradiography and initial biodistribution studies in rodents were performed, suggesting that [18F]12b was able to penetrate the blood-brain barrier (BBB) with high brain uptake (0.71% ID/g at 60 min post-injection) and no defluorination was observed. In vitro autoradiography study in brain slices of lipopolysaccharides (LPS)-induced neuroinflammation mice indicated that SEW2871, a specific S1PR1 ligand was able to reduce the uptake of [18F]12b, suggesting [18F]12b has S1PR1 specific binding. These initial results suggested that [18F]12b has potential to be an F-18 labeled radiotracer for imaging S1PR1 in the brain of the animal in vivo.
AB - Thirteen new sphingosine-1-phosphate receptor 1 (S1PR1) ligands were designed and synthesized by replacing azetidine-3-carboxylic acid moiety of compound 4 with new polar groups. The in vitro binding potency of these new analogs toward S1PR1 was determined. Out of 13 new compounds, four compounds 9a, 10c, 12b, and 16b displayed high S1PR1 binding potency with IC50 values of 13.2 ± 3.2, 14.7 ± 1.7, 9.7 ± 1.6, and 6.3 ± 1.3 nM, respectively; further binding studies of these four ligands toward S1PR2-5 suggested they are highly selective for S1PR1 over other S1PRs. The radiosynthesis of the lead radiotracer [18F]12b was achieved with good radiochemical yield (∼14.1%), high radiochemical purity (>98%), and good specific activity (∼54.1 GBq/μmol, decay corrected to the end of synthesis, EOS). Ex vivo autoradiography and initial biodistribution studies in rodents were performed, suggesting that [18F]12b was able to penetrate the blood-brain barrier (BBB) with high brain uptake (0.71% ID/g at 60 min post-injection) and no defluorination was observed. In vitro autoradiography study in brain slices of lipopolysaccharides (LPS)-induced neuroinflammation mice indicated that SEW2871, a specific S1PR1 ligand was able to reduce the uptake of [18F]12b, suggesting [18F]12b has S1PR1 specific binding. These initial results suggested that [18F]12b has potential to be an F-18 labeled radiotracer for imaging S1PR1 in the brain of the animal in vivo.
KW - Autoradiography
KW - Biodistribution
KW - F-18 radiotracer
KW - Multiple sclerosis
KW - PET
KW - Sphingosine-1-phosphate receptor 1
UR - http://www.scopus.com/inward/record.url?scp=85044618056&partnerID=8YFLogxK
U2 - 10.1016/j.ejmech.2018.03.035
DO - 10.1016/j.ejmech.2018.03.035
M3 - Article
C2 - 29604582
AN - SCOPUS:85044618056
SN - 0223-5234
VL - 150
SP - 796
EP - 808
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
ER -