Syntheses and in vitro biological evaluation of S1PR1 ligands and PET studies of four F-18 labeled radiotracers in the brain of nonhuman primates

Luo, Zonghua; Han, Junbin; Liu, Hui; Rosenberg, Adam J.; Chen, Delphine L.; Gropler, Robert J.; Perlmutter, Joel S.; Tu, Zhude

doi:10.1039/c8ob02609b

Syntheses and in vitro biological evaluation of S1PR1 ligands and PET studies of four F-18 labeled radiotracers in the brain of nonhuman primates

Journal Article · Thu Nov 15 00:00:00 EST 2018 · Organic and Biomolecular Chemistry

DOI:https://doi.org/10.1039/c8ob02609b· OSTI ID:1611052

^[1]; Han, Junbin ^[2]; ^[2]; ^[2]; Chen, Delphine L. ^[2]; Gropler, Robert J. ^[2]; ^[2]; ^[2]

Washington Univ., St. Louis, MO (United States); DOE/OSTI
Washington Univ., St. Louis, MO (United States)

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 [³²P]S1P competitive binding assays. Compounds 10a, 17a, 17b, and 24 exhibited high S1PR1 binding potencies with IC₅₀ values ranging from 3.9 to 15.4 nM and also displayed high selectivity for S1PR1 over other S1P receptor subtypes (IC₅₀ > 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 [¹⁸F]10a, [¹⁸F]17a, and [¹⁸F]17b but not [18F]24 crossed the blood brain barrier and had high initial brain uptake. Further validation of [¹⁸F]10a, [¹⁸F]17a, and [¹⁸F]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.

View Accepted Manuscript (DOE)

Research Organization:: Washington University, St. Louis, MO (United States)

Sponsoring Organization:: USDOE; USDOE Office of Science (SC)

Grant/Contract Number:: SC0008432

OSTI ID:: 1611052

Alternate ID(s):: OSTI ID: 1483021

Journal Information:: Organic and Biomolecular Chemistry, Journal Name: Organic and Biomolecular Chemistry Journal Issue: 47 Vol. 16; ISSN 1477-0520

Publisher:: Royal Society of ChemistryCopyright Statement

Country of Publication:: United States

Language:: English

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