Phase 1 Evaluation of 11 C-CS1P1 to Assess Safety and Dosimetry in Human Participants.

This study evaluated the safety, dosimetry, and characteristics of C-CS1P1, a radiotracer targeting sphingosine-1-phoshate receptor 1. Sphingosine-1-phoshate receptor 1 is of clinical interest because of its role in multiple sclerosis (and other conditions) with an expanding class of sphingosine-1-phosphate receptor modulators approved for relapsing multiple sclerosis. C-CS1P1 binds sphingosine-1-phosphate receptor 1 with high specificity and has shown promise in animal models of inflammatory diseases. C-CS1P1 was injected into 5 male and 6 female healthy participants. Ten participants were imaged with positron emission tomography using a multi-pass whole-body continuous-bed-motion acquisition and one had dedicated head and neck positron emission tomography and magnetic resonance imaging. Participants were continuously monitored for safety events. Organ time activity data were collected, integrated and normalized to the injected activity. Organ radiation doses as well as effective dose were computed using the adult male and female model in OLINDA v2.2. SUV images were evaluated for qualitative biodistribution. No adverse events were observed following the dose, including no bradycardia. The liver was the critical organ from dosimetry analysis (mean ± st. dev; Female: 23.12 ± 5.19 μSv/MBq; Male: 21.06 ± 1.63 μSv/MBq). The whole-body effective dose (as defined by ICRP103) was 4.18 ± 0.30 μSv/MBq in females and 3.54 ± 0.14 μSv/MBq in males. Using a maximum delivered dose of 740 MBq (20 mCi), the effective dose for females would be 3.1 mSv (0.31 rem) with a liver dose of 17.1 mSv (1.7 rem); the effective dose for males would be 2.6 mSv (0.26 rem) with a liver dose of 15.6 mSv (1.56 rem). Brain uptake was predominantly seen in gray matter and correlated with regional sphingosine-1-phosphate receptor 1 RNA expression (r = 0.84). These results support the safety of C-CS1P1 for evaluation of inflammation in human clinical populations. Dosimetry permits repeated measures in the same participants. Brain uptake correlates well with known target topography.