Radiosynthesis, In Vitro and In Vivo Evaluation of 18FCBD-2115 as a First-in-Class Radiotracer for Imaging 4R-Tauopathies

CBD-2115 was selected from a library of 148 compounds based on a pyridinyl-indole scaffold as a first-in-class 4R-tau radiotracer. In vitro binding assays showed 3HCBD-2115 had a KD value of 6.9 nM and a nominal Bmax of 500 nM in 4R-tau expressing P301L transgenic mouse tissue. In binding assays with human brain tissue homogenates, 3HCBD-2115 has a higher affinity (4.9 nM) for progressive supranuclear palsy specific 4R-tau deposits than 3Hflortaucipir (45 nM) or 3HMK-6240 (>50 nM). 18FCBD-2115 was reliably synthesized (3–11% radiochemical yield with molar activity of 27–111 GBq/μmol and >97% radiochemical purity). Dynamic PET imaging was conducted in mice, rats, and nonhuman primates, and all species showed initial brain uptake of 0.5–0.65 standardized uptake value with fast clearance from normal tissues. 3HCBD-2115 could be a useful lead radioligand for further research in 4R-tauopathies, and PET radiotracer development will focus on improving brain uptake and binding affinity.