Discovery of 6-(Fluoro-¹⁸F)-3-(1H-pyrrolo[2,3-c]pyridin-1-yl)isoquinolin-5-amine ([¹⁸F]-MK-6240): A Positron Emission Tomography (PET) Imaging Agent for Quantification of Neurofibrillary Tangles (NFTs)

Abstract

Neurofibrillary tangles (NFTs) made up of aggregated tau protein have been identified as the pathologic hallmark of several neurodegenerative diseases including Alzheimer's disease. In vivo detection of NFTs using PET imaging represents a unique opportunity to develop a pharmacodynamic tool to accelerate the discovery of new disease modifying therapeutics targeting tau pathology. Herein, we present the discovery of 6-(fluoro-(18)F)-3-(1H-pyrrolo[2,3-c]pyridin-1-yl)isoquinolin-5-amine, 6 ([(18)F]-MK-6240), as a novel PET tracer for detecting NFTs. 6 exhibits high specificity and selectivity for binding to NFTs, with suitable physicochemical properties and in vivo pharmacokinetics.

A report of the automated radiosynthesis of the tau positron emission tomography radiopharmaceutical, [18F]-THK-5351

“…Tau PET radiopharmaceuticals need to have a high‐binding affinity to neurofibrillary tangles with minimal nonspecific binding in the brain. Several carbon‐11 and fluorine‐18 labeled small molecule radiotracers such as [ 11 C]‐PBB3, [ 18 F]‐AV‐1451 (as known as T807), [ 18 F]‐T808, [ 18 F]‐MK‐6240, and [ 18 F]‐THK arylquinoline series allow measurement of the amount of tau protein deposits in the human brain (Figure ) . Of these tau PET radiopharmaceuticals, [ 18 F]‐AV‐1451 has been most extensively studied in tauopathy patients.…”

“…1 Over the past several years, many research groups have been working on the development of radiopharmaceuticals for imaging the tau pathology in the human brain. [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] Tau PET radiopharmaceuticals need to have a high-binding affinity to neurofibrillary tangles with minimal nonspecific binding in the brain. Several carbon-11 and fluorine-18 labeled small molecule radiotracers such as [ 11 C]-PBB3, [ 18 F]-AV-1451 (as known as T807), [ 18 F]-T808, [ 18 F]-MK-6240, and [ 18 F]-THK arylquinoline series allow measurement of the amount of tau protein deposits in the human brain ( Figure 1).…”

“…Several carbon-11 and fluorine-18 labeled small molecule radiotracers such as [ 11 C]-PBB3, [ 18 F]-AV-1451 (as known as T807), [ 18 F]-T808, [ 18 F]-MK-6240, and [ 18 F]-THK arylquinoline series allow measurement of the amount of tau protein deposits in the human brain ( Figure 1). 12,[17][18][19][20][21] Of these tau PET radiopharmaceuticals, [ 18 F]-AV-1451 has been most extensively studied in tauopathy patients. Our work and other recent reports have suggested that [ 18 F]-AV-1451 shows off-target binding in the brain.…”

Kinetic Modeling of the Tau PET Tracer 18F-AV-1451 in Human Healthy Volunteers and Alzheimer Disease Subjects

“…18 F-AV-1451 ( 18 F-T807, flortaucipir) (2) is a PET radiotracer with high affinity and specificity for tau aggregates, while lacking affinity for concomitant amyloid-b plaques in human AD (3,4). Several additional PET agents have been proposed for the imaging of tau in the brain, in particular 11 C-PBB3 (5,6), 18 F-THK-5117 (7), 18 F-T808 (8), 18 F-PI-2014 (9), and more recently 11 C-RO6924963, 11 C-RO6931643, 18 F-RO6958948 (10), 18 F-THK-5351 (11), 18 F-GTP1 (12), and 18 F-MK6240 (13), and have been or are being characterized and evaluated in humans. Currently, 18 F-AV-1451 has been the most widely used and characterized PET tracer (2)(3)(4)14,15) in clinical studies.…”

Tau Diagnostics and Clinical Studies

“…Recommendation improved tau imaging markers are required to standardize the methodology and apply it to clinical use, with new generation tracers such as Merck's MK-6240 (Walji et al 2016) or Piramal's PI-2620 (presented at the AD/ PD meeting, 2017, http://www.acimmune.com/content/ images/ADPD%202017%20_PI2620_Seibyl_final.pdf).…”