This article was originally published here
Org Biomol Chem. 2022 Jan 14. doi:10.1039/d1ob02225c. Online ahead of print.
Assessing the expression of sphingosine-1-phosphate receptor 1 (S1PR1) could be a unique tool to determine the neuroinflammatory status of central nervous system (CNS) disorders. Our preclinical results indicate that PET imaging with [11C]The CS1P1 radiotracer can quantitatively measure changes in S1PR1 expression in different animal models of inflammatory disease. Here, we developed a multi-step F-18 labeling strategy to synthesize the radiotracer [18F]FS1P1, sharing the same structure with [11C]CS1P1. We have explored a wide range of reaction conditions for nucleophilic radiofluorination starting with the key ortho-precursor to nitrobenzaldehyde 10. The tertiary amine additive TMEDA has been shown to be crucial in achieving high radiochemical yield of ortho-[18F]fluorobenzaldehyde [18F]12 starting with a small amount of precursor. Based on [18F]12, another four-step modification was applied in one pot to generate the target radiotracer [18F]FS1P1 with 30–50% radiochemical yield, >95% chemical and radiochemical purity, and high molar activity (37–166.5 GBq μmol-1, decay corrected at the end of the synthesis, EOS). Subsequently, the tissue distribution of [18F]FS1P1 in rats showed high cerebral uptake (ID% g-1) of 0.48 ± 0.06 at 5 min, and bone fixation of 0.27 ± 0.03, 0.11 ± 0.02 at 5 and 120 min respectively, suggesting no live defluorination. MicroPET studies have shown [18F]FS1P1 has a high macaque brain uptake with a standard uptake value (SUV) of approximately 2.3 at 120 min. Radiometabolite analysis of macaque plasma samples indicated that [18F]FS1P1 has good metabolic stability and no major radiometabolites confounded PET measurements of S1PR1 in non-human primate brain. Globally, [18F]FS1P1 is a promising F-18 S1PR1 radiotracer that merits further clinical study for human use.