MS565: A SPECT Tracer for Evaluating the Brain Penetration of BAF312 (Siponimod)

BAF312 (siponimod) is a sphingosine‐1‐phosphate (S1P) receptor modulator in clinical development for the treatment of multiple sclerosis, with faster organ/tissue distribution and elimination kinetics than its precursor FTY720 (fingolimod). Our aim was to develop a tracer to better quantify the penetration of BAF312 in the human brain, with the potential to be labeled for positron emission tomography (PET) or single‐photon emission computed tomography (SPECT). Although the PET radioisotopes 11C and 18F could have been introduced in BAF312 without modifying its structure, they do not have decay kinetics compatible with the time required for observing the drug′s organ distribution in patients. In contrast, the SPECT radioisotope 123I has a longer half‐life and would suit this purpose. Herein we report the identification of an iodinated derivative of BAF312, (E)‐1‐(4‐(1‐(((4‐cyclohexyl‐3‐iodobenzyl)oxy)imino)ethyl)‐2‐ethylbenzyl)azetidine‐3‐carboxylic acid (18, MS565), as a SPECT tracer candidate with affinity, S1P receptor selectivity, overall physicochemical properties, and blood pharmacokinetics similar to those of the original molecule. A whole‐body autoradiography study performed with [14C]MS565 subsequently confirmed that its organ distribution is similar to that of BAF312. This validates the selection of MS565 for 123I radiolabeling and for use in imaging studies to quantify the brain penetration of BAF312. Exposing siponimod: BAF312 is a drug candidate for the treatment of multiple sclerosis. Replacement of its trifluoromethyl group by iodine did not affect organ/tissue distribution or pharmacokinetics, and led to the prospective single‐photon emission computed tomography (SPECT) imaging agent MS565. The ability of MS565 to mimic BAF312 was confirmed by whole‐body autoradiography, using their 14C isotopomers.