Radiosynthesis, <i>In Vitro</i> and <i>In Vivo</i> Evaluation of [¹⁸F]CBD-2115 as a First-in-Class Radiotracer for Imaging 4R-Tauopathies

Abstract

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 [³H]CBD-2115 had a <i>K</i>_D value of 6.9 nM and a nominal <i>B</i>_max of 500 nM in 4R-tau expressing P301L transgenic mouse tissue. In binding assays with human brain tissue homogenates, [³H]CBD-2115 has a higher affinity (4.9 nM) for progressive supranuclear palsy specific 4R-tau deposits than [³H]flortaucipir (45 nM) or [³H]MK-6240 (>50 nM). [¹⁸F]CBD-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. [³H]CBD-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.