Brain Distribution of MS565, an Imaging Analogue of Siponimod (BAF312), in Non-human Primates (P1.168)

OBJECTIVE: To investigate the brain distribution and kinetics of siponimod (BAF312) by using an iodine-labeled analogue of siponimod, [ 123 I]MS565, and single photon emission computed tomography (SPECT) in non-human primates (NHP). BACKGROUND: Siponimod is a selective sphingosine 1-phosphate (S1P-1,5) receptor modulator currently in Phase 3 development for secondary progressive multiple sclerosis. Experimental studies in rats showed that siponimod penetrates into the CNS (4-8 hours post-administration) and may result in direct beneficial effects by acting on S1P-1 and/or -5 receptor expressing cells such as astrocytes and oligodendrocytes. DESIGN/METHODS: [ 123 I]MS565 (radioactive half-life of 13.2-hours) was administered to 2 adult male rhesus NHPs ( Macaca mulatta ), as single intravenous bolus. SPECT studies were performed using a MollyQ camera (Neurophysics Inc., Shirley, MA, USA). Brain penetration was assessed by serial dynamic scanning over a 2-day period following radiotracer injection. Scan duration was approximately 8-hours on Day 1 and 2-hours on Day 2 with a 24-hour interval between the last scan on Day 1 and the first scan on Day 2. SPECT images were corrected for motion, decay and tissue attenuation. The scans were reconstructed and analyzed using PMOD 3.405 software. Standardized uptake values (SUV) were calculated by normalizing for injected activity and body weight. Subsequently, images were co-registered to a MRI template for volumes of interest extraction, time-activity curves generation and brain penetration estimation. Blood samples were taken to determine the radio-metabolite concentration in plasma. RESULTS: Following intravenous bolus injection, [ 123 I]MS565 penetrated NHP brain with highest concentration in brain of 0.008-0.014 %ID/mL at around 24-hours post-injection. Peak SUV values of around 0.6-0.8 were also determined during day 2 imaging session. Radiotracer metabolism in plasma was slow and at 24-hours post-injection ~70% of parent compound was still present in rhesus monkey plasma. CONCLUSIONS: [ 123 I]MS565 is a promising SPECT imaging agent to investigate the potential CNS distribution of siponimod. Whole-body imaging is ongoing to obtain radiation absorbed dose estimates for [ 123 I]MS565. Study Supported by: Novartis Pharma AG Disclosure: Dr. Tavares has received personal compensation for activities with Molecular Neuroimaging as an employee. Dr. Barret has received personal compensation for activities with Molecular Neuroimaging as an employee. Dr. Alagille has received personal compensation for activities with Molecular NeuroImaging Inc. as an employee. Dr. Morley has received personal compensation for activities with Molecular Neuroimaging Inc. as an employee. Dr. Papin has received personal compensation for activities with Molecular NeuroImaging Inc. as an employee. Dr. Maguire has received personal compensation for activities with Novartis as an employee. Dr. Briard has received personal compensation for activities with Novartis as an employee. Dr. Auberson has received personal compensation for activities with Novartis. Dr. Tamagnan has received personal compensation for activities with Molecular Neuroimaging as an employee.