期刊
ACS CHEMICAL NEUROSCIENCE
卷 12, 期 4, 页码 596-602出版社
AMER CHEMICAL SOC
DOI: 10.1021/acschemneuro.0c00801
关键词
PET; tau; 4R-tau; fluorine-18; CBD-2115
资金
- National Institute on Ageing of the NIH [R01AG054473, R01AG052414]
- Azrieli Foundation
- Canada Foundation for Innovation
- Ontario Research Fund
- Canada Research Chairs Program
- National Institute on Neurological Disorders and Stroke (NINDS)
- NIA [1U19NS110456]
- Michael J. Fox Foundation [14605]
- Rainwater Charitable Foundation (Tau Consortium) [14605]
- Cerveau Technologies
CBD-2115, a first-in-class 4R-tau radiotracer, showed high binding affinity and reliable synthesis, holding potential for further research on 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 [H-3]CBD-2115 had a K-D value of 6.9 nM and a nominal B-max of 500 nM in 4R-tau expressing P301L transgenic mouse tissue. In binding assays with human brain tissue homogenates, [H-3]CBD-2115 has a higher affinity (4.9 nM) for progressive supranuclear palsy specific 4R-tau deposits than [H-3]flortaucipir (45 nM) or [H-3]MK-6240 (>50 nM). [F-18]CBD-2115 was reliably synthesized (3-11% radiochemical yield with molar activity of 27-111 GBq/mu mol 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. [H-3]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.
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