Development of triazole-based positron emission tomography ligands targeting glutaminyl cyclases (QCs) in the brain

Glutaminyl cyclases (QCs), including secreted sQC and Golgi-resident gQC, catalyze pyroglutamate formation and play a crucial role in Alzheimer's disease (AD). Here, we present the development of two triazole-cored QC-targeting PET ligands, [¹⁸F]SEN177 ([¹⁸F]8) and [¹⁸F]QP5020 ([¹⁸F]9). Compound 9 displayed superior binding potency toward both sQC and gQC with IC₅₀ values of 30.6 and 9.2 nM, respectively, outperforming 8 (sQC IC₅₀ = 231.6 nM, gQC IC₅₀ = 67.1 nM). In vitro autoradiography studies in rat brain sections revealed specific binding of both radioligands to QCs with different regional distributions. Notably, [¹⁸F]9 demonstrated increased binding in cortical regions of a transgenic AD mouse, which correlated with Aβ plaque density, suggesting its utility in detecting QCs alteration in vitro. However, both ligands showed limited brain uptake (<0.2 % ID/g at 2 min post-injection) in murine biodistribution studies. PET imaging with [¹⁸F]8 in transgenic mice demonstrated low brain uptake, but pretreatment with unlabeled 9 reduced brain radioactivity by 26.2 %, indicating specific binding to QCs in vivo. These findings provide a foundation for refining triazole-cored QCs inhibitors to develop new PET ligands with enhanced brain pharmacokinetics and isoform selectivity.