In vivo Characterization of Four ¹⁸F-Labeled S1PR1 Tracers for Neuroinflammation

The sphingosine-1-phosphate receptor 1 (S1PR1) is an important biomarker for imaging inflammation in the central nervous system (CNS). Herein, we report our recent evaluation of four ¹⁸F-labeled S1PR1 tracers (¹⁸F-TZ43113, ¹⁸F-TZ35104, ¹⁸F-TZ4877, and ¹⁸F-TZ4881) in a rat model of multiple sclerosis (MS).

MicroPET studies of each tracer's uptake and kinetics were performed in an experimental autoimmune encephalomyelitis (EAE) rat model of MS to quantify upregulated S1PR1 expression in the lumbar spinal cord of EAE rats. Western blot analysis was conducted to confirm the differences in the expression of S1PR1 protein level between EAE and sham rats. Radiometabolite analysis was performed for the most promising candidate in rats.

All four S1PR1 tracers detected increased S1PR1 levels in response to neuroinflammation in the lumbar spinal cord of EAE rats, which was supported by western blot results. The ranked order of tracer uptake in rat spinal cord was ¹⁸F-TZ4877 > ¹⁸F-TZ4881 > ¹⁸F-TZ35104 > ¹⁸F-TZ43113. ¹⁸F-TZ4877 had the highest uptake of the four tracers and showed good kinetic modeling fits in rat spinal cord using an image-based method of arterial blood input function. Radiometabolite analysis of ¹⁸F-TZ4877 showed good in vivo stability with no major radiometabolite accumulation in the rat brain.

Among these four new PET tracers, ¹⁸F-TZ4877 showed the most favorable profile for assessing S1PR1 expression in the EAE rat model of MS. Further characterization of these radiotracers in other models of neuroinflammation is warranted to identify a promising ¹⁸F-labeled tracer for imaging S1PR1 in vivo.