Synthesis and evaluation of 2-pyrrolopyridinylquinoline derivatives as selective tau PET tracers for the diagnosis of Alzheimer's disease

Introduction: [¹⁸F]THK-5351 was originally developed as a positron emission tomography (PET) imaging tracer for the detection of accumulated tau proteins, the pathological hallmark of Alzheimer's disease (AD). However, clinical studies of [¹⁸F]THK-5351 revealed the existence of off-target binding to monoamine oxidase-B (MAO-B). To overcome this off-target binding, in this work, we synthesized and evaluated 2-pyrrolopyridinylquinoline (PPQ) derivatives as selective tau PET imaging tracers. Methods: The core structure of PPQ derivatives was synthesized mainly using the Buchwald-Hartwig amination coupling reaction. All derivatives were evaluated for binding affinity towards tau and MAO-B by in vitro competitive binding assay. Radiosynthesis of PPQ derivatives was performed by ¹⁸F-radiolabeling of their tosylate precursors with activated [¹⁸F]KF/Kryptofix222 complex in dimethylsulfoxide by heating at 110 °C for 10 min. The biological properties of these [¹⁸F]PPQ derivatives were characterized by in vitro autoradiography of postmortem AD brain sections and by assay of ex vivo biodistribution in mice. Results: The PPQ derivatives were synthesized, with yields of 49–84%. In vitro competitive binding assay revealed that two novel PPQ derivatives—PPQ8 and PPQ9—demonstrated high binding affinity for tau (IC₅₀ = 4.9 and 6.9 nM, respectively). The radiosynthesis of [¹⁸F]PPQ8 and [¹⁸F]PPQ9 yielded 1.4% and 50.1% isolated non-decay corrected radiochemical yield, respectively, with >99% radiochemical purity. The molar radioactivities of [¹⁸F]PPQ8 and [¹⁸F]PPQ9 were 16.9 and 64.8 GBq/μmol, respectively. The in vitro and ex vivo biological characterization of [¹⁸F]PPQ8 and [¹⁸F]PPQ9 revealed that these tracers were selective for tau in AD brain sections without off-target binding, and they furthermore demonstrated brain uptake in normal mice. Conclusions: ¹⁸F-labeled PPQ derivatives improved binding affinity and selectivity for tau aggregates in AD. Further structural optimization to improve pharmacokinetics for potent tau PET imaging tracers is required.