Radiosynthesis and evaluation of a fluorine-18 radiotracer [18F] for imaging sphingosine-1-phosphate receptor 1

Assessment of sphingosine-1-phosphate receptor 1 (S1PR1) expression could be a unique tool to determine the neuroinflammatory status for central nervous system (CNS) disorders. Our preclinical results indicate that PET imaging with [C-11]CS1P1 radiotracer can quantitatively measure S1PR1 expression changes in different animal models of inflammatory diseases. Here we developed a multiple step F-18 labeling strategy to synthesize the radiotracer [F-18]FS1P1, sharing the same structure with [C-11]CS1P1. We explored a wide range of reaction conditions for the nucleophilic radiofluorination starting with the key ortho-nitrobenzaldehyde precursor 10. The tertiary amine additive TMEDA proved crucial to achieve high radiochemical yield of ortho-[F-18]fluorobenzaldehyde [F-18]12 starting with a small amount of precursor. Based on [F-18]12, a further four-step modification was applied in one-pot to generate the target radiotracer [F-18]FS1P1 with 30-50% radiochemical yield, >95% chemical and radiochemical purity, and a high molar activity (37-166.5 GBq mu mol(-1), decay corrected to end of synthesis, EOS). Subsequently, tissue distribution of [F-18]FS1P1 in rats showed a high brain uptake (ID% g(-1)) of 0.48 +/- 0.06 at 5 min, and bone uptake of 0.27 +/- 0.03, 0.11 +/- 0.02 at 5, and 120 min respectively, suggesting no in vivo defluorination. MicroPET studies showed [F-18]FS1P1 has high macaque brain uptake with a standard uptake value (SUV) of similar to 2.3 at 120 min. Radiometabolite analysis of macaque plasma samples indicated that [F-18]FS1P1 has good metabolic stability, and no major radiometabolite confounded PET measurements of S1PR1 in nonhuman primate brain. Overall, [F-18]FS1P1 is a promising F-18 S1PR1 radiotracer worthy of further clinical investigation for human use.

Automated summary

The study has developed a new multiple step F-18 labeling strategy, successfully synthesized the [F-18]FS1P1 radiotracer with the same structure as the existing tracer [C-11]CS1P1. The radiotracer showed high metabolic stability and effective method for detecting neuroinflammatory status in animal models.