18F-THK523: a novel in vivo tau imaging ligand for Alzheimer's disease

Abstract

While considerable effort has focused on developing positron emission tomography β-amyloid imaging radiotracers for the early diagnosis of Alzheimer's disease, no radiotracer is available for the non-invasive quantification of tau. In this study, we detail the characterization of (18)F-THK523 as a novel tau imaging radiotracer. In vitro binding studies demonstrated that (18)F-THK523 binds with higher affinity to a greater number of binding sites on recombinant tau (K18Δ280K) compared with β-amyloid(1-42) fibrils. Autoradiographic and histofluorescence analysis of human hippocampal serial sections with Alzheimer's disease exhibited positive THK523 binding that co-localized with immunoreactive tau pathology, but failed to highlight β-amyloid plaques. Micro-positron emission tomography analysis demonstrated significantly higher retention of (18)F-THK523 (48%; P < 0.007) in tau transgenic mice brains compared with their wild-type littermates or APP/PS1 mice. The preclinical examination of THK523 has demonstrated its high affinity and selectivity for tau pathology both in vitro and in vivo, indicating that (18)F-THK523 fulfils ligand criteria for human imaging trials.

Novel 18F-Labeled Arylquinoline Derivatives for Noninvasive Imaging of Tau Pathology in Alzheimer Disease

“…Then, 2 M HCl was added to the solution, followed by an additional 3-min reaction for deprotection of the hydroxyl group. After neutralization with 4 M AcOK, the product was purified by semipreparative high-performance liquid chromatography (HPLC) 18 F-THK-523 and 18 F-FDDNP were also prepared in a manner similar to the one described above using the corresponding tosylate precursors reported previously (15,25,26). 11 C-PiB was radiolabeled using its precursor (2-(4-aminophenyl)-6-methoxymethoxybenzothiazole) and 11 C-methyl triflate, as previously described (27).…”

“…Several researchers have focused on developing radiotracers for imaging tau pathology in the human brain (10)(11)(12)(13)(14)(15)(16)(17). Tau imaging radiotracers need to cross the blood-brain barrier and to have a high binding affinity to NFTs with minimal nonspecific binding (18).…”

“…Consequently, we identified a series of novel quinoline and benzimidazole derivatives that bind NFTs and, to a lesser extent, Ab plaques (10). Serial analyses of these compounds led to the design and synthesis of the novel tau imaging agent 18 F-6-(2-fluoroethoxy)-2-(4-aminophenyl)quinoline ( 18 F-THK-523) (15,17). Preclinical analyses of 18 F-THK-523 indicated that this tracer selectively labels tau pathology in the AD brain.…”

PET Approaches for Diagnosis of Dementia

“…18 F-THK-523 was developed as a potential in vivo imaging probe for pathology and was reported to accumulate in regions containing a high attenuation of protein deposits. 62 This tracer is now being used in patients with AD. Some forms of FTD, PSP, and CBD are also characterized by pathologic accumulation of protein.…”

A Novel Kernel-Based Regularization Technique for PET Image Reconstruction

“…Nowadays, a major set of PET applications is in oncology [5], cardiac imaging [6], and brain imaging [7]. With the developments of specific radiotracers, several applications of PET in neurology have been found during the last few years, such as dopamine neurotransmitter imaging in Parkinson's disease and tau imaging [8] in Alzheimer's disease. PET works by a radioactive tracer that has been introduced into the body, decaying to emit a positron β+, which can only travel a few millimeters (the positron range [9]), before colliding with an electron.…”