Kinetic Modeling of a Novel Putative Sphingosine‐1‐Phosphate Receptor 1 ( S 1 PR 1) Radiotracer 18 F TZ 82112 in Nonhuman Primates

Sphingosine-1-phosphate receptors (S1PRs) play an important regulatory role in various biological processes, including immune responses and neurodegeneration. We report the binding specificity of an S1PR1 PET radiotracer, 18FTZ82112, via in vitro autoradiography blocking studies with S1PR1 modulators in human and rat brain tissues and evaluate the tracer kinetics via kinetic modeling in nonhuman primates (NHPs) to assess its potential for clinical translation. A total of 12 scans were performed in four male macaques (M 1-4). Each macaque had 1-4 baseline scans and at least one blocking scan in three macaques. Arterial input function (AIF) was obtained from M2 and M3 under baseline conditions and M3 after pretreatment with cold TZ82112. The metabolite-corrected plasma AIF was applied to several kinetic models-one-tissue compartment (1TC) and 2TC, and Graphical Logan Analysis. Five candidate reference regions, namely the whole cerebellum, brain stem, occipital cortex, corpus callosum, and cerebral white matter, were investigated for deriving the standardized uptake value ratios (SUVr). The 2TC with four parameters (2TC4K) with blood volume (Vb) fitting is the most suitable kinetic model for evaluating 18FTZ82112 kinetics. Pretreatment with unlabeled TZ82112 reduced uptake of 18FTZ82112, demonstrating specific binding in all analyzed regions, including potential reference regions. Reduced tracer uptake in in vitro blocking studies further confirmed the tracer specificity to S1PR1. We concluded that accurate 18FTZ82112 quantification requires AIF measurements, owing to the lack of a suitable reference region; no reference region modeling approach or SUVr would be appropriate. Fast tracer uptake and high VT values, particularly in the prefrontal cortex and striatum, indicated that 18FTZ82112 enters the brain quickly and has high S1PR1-specific binding in NHP brain. The current findings further support 18FTZ82112 as a good PET radiotracer for the quantification of S1PR1 in the brain, provided an AIF is employed.