2. Academic Validation
  3. Discovery of a novel tau PET tracer: Design, synthesis, radio-labeling, and preclinical evaluations

Discovery of a novel tau PET tracer: Design, synthesis, radio-labeling, and preclinical evaluations

  • Eur J Med Chem. 2026 Mar 5:305:118542. doi: 10.1016/j.ejmech.2025.118542.
Dongping Yao 1,  Ni Zhang 2,  Qian Yao 1,  Yongmei Xie 1,  Rong Tian 3,  Xiaoai Wu 4,  Weihong Kuang 5
Affiliations

Affiliations

  • 1 Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China.
  • 2 Mental Health Center, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China.
  • 3 Department of Nuclear Medicine, Laboratory of Clinical Nuclear Medicine, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China.
  • 4 Department of Nuclear Medicine, Laboratory of Clinical Nuclear Medicine, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China. Electronic address: [email protected].
  • 5 Mental Health Center, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China. Electronic address: [email protected].
PMID: 41512538 DOI: 10.1016/j.ejmech.2025.118542
Abstract

Nitrogen-containing heterocyclic small molecule derivatives have been proved to possess potent affinity with tau aggregates. A series of imidazo[1,2-a]pyridine analogues were designed and synthesized for the screen of potential highly selective tau targeted PET tracers. Structure activity relationship study of these compounds led to the discovery of compound 28, which showed high affinity with tau aggregates (Ki = 0.99 nM). Compound 28 also displayed fast pharmacokinetic properties which are suitable to be developed as PET tracers. Based on the direct SNAr radiofluorination, 18F-28 was successfully produced with high radiochemical yield. In vitro stability tests and log D7.4 measurement indicated 18F-28 hold suitable physicochemical parameters for blood-brain-barrier (BBB) penetration and in vivo PET brain imaging. In micro-PET imaging studies, high initial brain uptake was observed with 18F-28 in normal mice and P301L transgenic mice, as well as a fast clearance from brain. 18F-28 was also evaluated in non-human primates, which also displayed a fast in and fast out accumulation in the brain. According to the autoradiographic analysis of 18F-28 with human brain tissues, positive deposits in temporal lobe can be confirmed, which is well agreed with immunohistochemistry results with tau-antibodies. Therefore, the preclinical results revealed compound 28 holds the potential to be developed as a potent and selective tau aggregate targeted PET tracer, and further optimizations and evaluations may still be needed.

Keywords

Alzheimer's disease; Micro-PET imaging; Radio-labeling; Tau; Tracer.

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