PI-2620 Lead Optimization Highlights the Importance of Off-Target Assays to Develop a PET Tracer for the Detection of Pathological Aggregated Tau in Alzheimer’s Disease and Other Tauopathies

Abstract

The first candidate PI-2014 was tested in healthy controls and subjects with Alzheimer’s disease (AD). As PI-2014 displayed off-target binding to monoamine oxidase A (MAO-A), a new lead with improved binding to Tau and decreased MAO-A binding was required. For compound optimization, Tau binding assays based on both human AD brain homogenate and Tau-paired helical filaments were employed. Furthermore, two MAO-A screening assays based on (1) human-recombinant MAO-A and (2) displacement of 2-fluoro-ethyl-harmine from mouse brain homogenate were employed. Removing the N-methyl group from the tricyclic core resulted in compounds displaying improved Tau binding. For the final round of optimization, the cyclic amine substituents were replaced by pyridine derivatives. PI-2620 (2-(2-fluoropyridin-4-yl)-9H-pyrrolo­[2,3-b:4,5-c′]­dipyridine) emerged as a best candidate displaying high Tau binding, low MAO-A binding, high brain uptake, and fast and complete brain washout. Furthermore, PI-2620 showed Tau binding on brain sections from corticobasal degeneration, progressive supranuclear palsy, and Pick’s disease.

Synthesis and In Vitro and In Vivo Evaluation of 18F-Labeled Positron Emission Tomography Tracers for Imaging Aβ Plaques

“…Changing the position and number of N atoms in existing tracers is expected to overcome the shortcomings of existing tracers. − With modification, the ligand’s site of interaction and hydrophilicity will be changed, which might contribute to better properties for PET tracers without affecting previous affinity, such as modifying PK11195 to ER176 for translocator protein imaging and AV1451, PI-2620, and RO-948 for tau imaging. , Meanwhile, the substitution is more efficient for the development of new tracers than trying to produce a completely new moiety. Benzothiophene and stilbene structures are two major skeletons for Aβ tracers.…”

Synthesis and Preclinical Evaluation of 2-(4-[18F]Fluorophenyl)imidazo[1,2-h][1,7]naphthyridine ([18F]FPND-4): An Aza-Fused Tricyclic Derivative as Positron Emission Tomography Tracer for Neurofibrillary Tangle Imaging

“…-iodaneylidene)-6,10-dioxaspiro [4.5]decane-7,9-dione (17). Compound 17 was prepared according to the previously reported method, yielding a light yellow solid (16.1 mg, 18.2%).…”

“…Setting the NFTs as the biomarker, PET imaging may provide precise and real-time information for detecting neurodegeneration before the onset of cognitive symptoms and monitoring the disease progression consecutively. , Recently, several Tau-specific PET tracers with high binding to NFTs and favorable selectivity over Aβ plaques have been disclosed, such as [ 18 F] Flortaucipir (also known as [ 18 F] T807 or [ 18 F] AV-1451 ), [ 18 F] T808 , [ 18 F] GTP-1 , [ 18 F] THK5351 , [ 18 F] S-16 , [ 18 F] RO6958948 , [ 18 F] MK6240 , [ 18 F] APN1607 , [ 18 F] PI-2620 , and [ 18 F] JNJ-067 . Whereas, some recent clinical studies have shown that there are still some limitations of these radiotracers when detecting Tau pathology in AD patients, including slight metabolic defluorination, off-target binding to monoamine oxidase A/B (MAO-A/B), choroid plexus, and other targets. − One practical and feasible strategy is to screen and modify new scaffolds to overcome these limitations and promote the development of small-molecule-based Tau ligands.…”

Amyloid and Tau Positron Emission Tomography Imaging in Alzheimer’s Disease and Other Tauopathies

“…[ 3 H]PI-2620 has also been shown to bind to 4R tau, thus allowing the assessment of patients with PSP (Figure 2B; Kroth et al, 2019;Brendel et al, 2020;Song et al, 2021). Additionally, [ 18 F]PI-2620 has shown lower binding affinity to monoamine oxidase A (MAO-A) of AD brain homogenates (Kroth et al, 2021). Zhou et al (2021) investigated the binding properties of PET tracers [ 18 F]PI-2620, [ 18 F]CBD2115, [ 18 F]PM-PBB3, and [ 18 F]MK6240 binding to CBD tau by using in silico studies where high affinity binding for the core and an entry site of the 4R tau fibril were detected.…”