THK-5351

THK-5351 is a quinoline-derived compound developed as a precursor for the radiotracer THK-5351 F-18, which was initially designed for imaging neurofibrillary tangles (NFTs) in Alzheimer's disease. While initially thought to be specific for tau protein fibrils, subsequent research revealed that it also binds significantly to monoamine oxidase B (MAO-B), complicating its interpretation as a pure tau imaging agent. ## Chemical Properties and Structure THK-5351 has the molecular formula C18H18FN3O2 with a molecular weight of 327.36. It is structurally characterized as 2-(6-methylaminopyridine-3-yl)-6-((S)-3-fluoro-2-hydroxy-propyloxy)quinoline[5]. The compound contains one defined stereocenter and is an S-enantiomer, which was developed to improve the pharmacokinetics of arylquinoline derivatives[4]. ## Development and Research Applications THK-5351 was developed through compound optimization of arylquinoline derivatives[8]. In vitro studies demonstrated that THK-5351 has higher binding affinity for hippocampal homogenates from Alzheimer's disease brains compared to its predecessor THK-5117[8]. It also showed faster dissociation from white matter tissue, which is advantageous for brain imaging applications[4]. When radiolabeled with fluorine-18 to create 18F-THK5351, the compound was initially used in positron emission tomography (PET) studies to visualize neurofibrillary pathology in Alzheimer's disease patients[4][8]. However, subsequent research revealed a significant limitation: 18F-THK5351 also binds strongly to monoamine oxidase B (MAO-B)[3]. ## Binding Properties and Limitations A key study demonstrated that administration of selegiline, a MAO-B inhibitor, significantly reduced 18F-THK5351 uptake in the brain by 36.7% to 51.8%[3]. This finding indicated that a substantial portion of the 18F-THK5351 PET signal was attributable to MAO-B binding rather than exclusively to tau pathology. The greatest reduction in uptake after selegiline administration was observed in the thalamus (51.8%) and basal ganglia (51.4%), areas with high MAO-B availability[3]. This dual binding property has led researchers to reinterpret 18F-THK5351 PET signals as potentially indicating neuroinflammation (via MAO-B expression in reactive astrocytes) in addition to tau pathology[7]. Despite this limitation, some studies suggest that 18F-THK5351 uptake might still be a useful predictor of cognitive decline in certain patient populations[10]. ## Clinical Applications Despite its limitations as a pure tau tracer, 18F-THK5351 PET has been used in clinical research to: 1. Study the relationship between tau/neuroinflammation and cortical atrophy in Alzheimer's disease and mild cognitive impairment[6] 2. Predict cognitive decline in amyloid-negative amnestic mild cognitive impairment patients[10] 3. Investigate atypical presentations of Alzheimer's disease[7] The compound represents an important step in the development of tau imaging agents, though newer generation tracers with improved specificity have since been developed.

Other names

2-(6-methylaminopyridine-3-yl)-6-((S)-3-fluoro-2-hydroxy-propyloxy)quinoline