Development of a Novel ¹⁸F‐Labeled Radioligand for Imaging Translocator Protein With Positron Emission Tomography

Translocator protein 18 kDa (TSPO) is a well‐established biomarker of neuroinflammation and is implicated in the pathophysiology of various neurodegenerative diseases, including Alzheimer's disease (AD). Despite existing radioligands, there remains a critical need for novel TSPO‐targeted positron emission tomography (PET) tracers with improved binding specificity, higher brain uptake, and favorable pharmacokinetics.

We designed and synthesized a class of novel TSPO ligand candidates. Following in vitro binding affinity screening, the lead Compound 3 (TSPO‐1118) was radiolabeled with fluorine‐18. [¹⁸F]3 ([¹⁸F]TSPO‐1118) was evaluated in two transgenic AD mouse models (3xTg and APP/PS1) and compared to age‐matched wild‐type (WT) controls. Biodistribution and radiometabolite analyses were conducted in CD‐1 mice to assess brain penetration and metabolic stability.

Compound 3 (TSPO‐1118) demonstrated superior binding affinity for TSPO (K_i = 2.3 nM), outperforming both other analogs in the series and the benchmark tracer GE180. [¹⁸F]3 ([¹⁸F]TSPO‐1118) exhibited significantly higher brain uptake in both 3xTg and APP/PS1 mice relative to WT controls, including the cortex, thalamus, cerebellum, and hippocampus (p < 0.05 to < 0.01, Student's two‐tailed t‐test), consistent with elevated TSPO expression in disease models. The tracer also displayed favorable brain kinetics, high specific binding, and metabolic stability in vivo.

[¹⁸F]3 ([¹⁸F]TSPO‐1118) represents a promising next‐generation PET radioligand for imaging TSPO with high affinity, robust brain uptake, and specificity in preclinical models of neurodegeneration. Its favorable profile supports further translational development toward clinical application in neuroinflammatory and neurodegenerative disorders.