Candidate PET Radioligand Development for Neurofibrillary Tangles: Two Distinct Radioligand Binding Sites Identified in Postmortem Alzheimer’s Disease Brain

Abstract

[18F]THK-523 and [18F]807 are promising radioligands for imaging neurofibrillary tangles (NFTs) with positron emission tomography (PET) in neurodegenerative diseases, such as Alzheimer’s disease (AD) and traumatic brain injury. Although [18F]THK-523 and [18F]T807 are considered high-affinity selective radioligands for NFTs, uncertainty has existed as to whether PET radioligands for imaging NFTs bind to the same molecular site because in vitro assays for ligands binding to NFTs have been lacking. We labeled THK-523 and T807 with tritium to serve as reference radioligands for in vitro binding assays with AD brain homogenates for newly synthesized ligands. With these radioligands, we identified two distinct binding sites for small molecules, one site with high affinity for THK-523 and the other with high affinity for T807. Moreover, binding assays with [3H]PIB confirmed that the two newly identified binding sites are also distinct from the thioflavin-T binding site where all current clinically useful PET radioligands for imaging β-amyloid plaque bind with high affinity. The two newly identified binding sites are considered to reside on NFTs rather than on β-amyloid plaques. Furthermore, we applied all three binding assays to a set of newly prepared compounds, based on chain modifications to THK-523. Some compounds with high affinity and selectivity for the THK-523 binding site emerged from this set, including one with amenability to labeling with fluorine-18, namely, ligand 10b.

Comparative binding properties of the tau PET tracers THK5117, THK5351, PBB3, and T807 in postmortem Alzheimer brains

“…Three previous studies have compared the different tau PET tracer families in two-by-two batches. The first compared 11 C-PBB3 and 18 F-AV1451 [ 25 ]; the second compared 3 H-AV1451 and 3 H-THK523 (one of the first-generation THK compounds) [ 26 ]; and the third compared 18 F-T808 (in the same family as T807) and THK5105 (THK family compound) [ 27 ].…”

“…Cai et al designed a study to develop a new tau deposit tracer with high affinity compared THK523 and T807 with PIB. Their study suggested that THK523 and T807 have two separate binding sites on the NFTs and that those binding sites differ from the thioflavin-T binding site targeted by amyloid PET tracers [ 26 ]. In our study, both 11 C-THK5351 and 18 F-T807 showed binding in the basal ganglia region.…”

Quinuclidine and DABCO Enhance the Radiofluorination of 5‐Substituted 2‐Halopyridines

“…As part of our ongoing program to develop PET radiotracers for imaging neurofibrillary tangles, we were initially interested in the radiofluorination of tert ‐butyl [6‐(6‐chloropyridin‐3‐yl)naphthalen‐2‐yl]carbamate ( 7 ) to produce [ 18 F]6‐(6‐fluoropyridin‐3‐yl)naphthalen‐2‐amine ([ 18 F] 6 ) in two steps, namely radiofluorination with 18 F – ‐K + ‐K 2.2.2 followed by removal of the Boc protecting group (Table ). This labeling strategy gave no [ 18 F] 6 in DMF at 120 °C (entry 1) or in DMSO at 200 °C (entry 2) and very low yield in DMSO at 220 °C (entry 3).…”

KOt-Bu-promoted selective ring-opening N-alkylation of 2-oxazolines to access 2-aminoethyl acetates and N-substituted thiazolidinones

“…However, the ring-opening N-alkylation of 2-oxazolines to produce 2-aminoethyl acetate derivatives under basic conditions has not been reported. Thiazolidinone derivatives are important moieties in functional materials and natural products [12][13][14], such as latrunculin that has been obtained from the sponge Cacospongia mycofijiensis [15]. Convenient syntheses of thiazolidinone derivatives are highly attractive to synthetic chemists.…”