Abstract
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Objectives Neurofibrillary tangles (NFTs) load, particularly tau pathology, is linked to cognitive decline in neurodegenerative diseases including Alzheimer’s disease (AD). Non-invasive characterization of NFTs by positron emission tomography (PET) can facilitate longitudinal disease progression and therapy monitoring. We have developed [18F]MK-6240 as a new PET tracer for imaging NFTs, and performed preclinical characterization, aiming to determine selectivity, sensitivity and in vivo brain kinetics of the tracer. Following successful preclinical validation, we performed whole-body PET imaging in humans to estimate radiation burden.
Methods In vitro binding assays in brain homogenates were conducted using tissue of AD brain donors to evaluate tracer affinity for NFTs. Selectivity for Aβ as well as for >100 recombinant human neurological targets was assessed by pharmacological screening. PET studies were performed in rhesus monkeys using [18F]MK-6240 to evaluate tracer kinetics and distribution in brain. Total distribution volume (VT) was assessed by compartmental modeling using metabolite corrected input function at baseline and after self-blockade. Three healthy human subjects underwent whole-body PET for 5 h each after injection of 180 ± 0.3 MBq of [18F]MK-6240 to estimate radiation exposure (effective dose).
Results MK-6240 has high affinity (Ki = 0.3 nM) and has >30,000-fold selectivity to NFTs (Aβ Ki = 10 µM, < 50% inhibition at 10µM for >100 neurological targets). In monkey PET studies, [18F]MK-6240 displays rapid uptake with SUV of 2-3, followed by a quick washout and a homogeneous distribution in the brain. [18F]MK-6240 VT is ~ 5 mL•cm-3 across brain regions and stabilizes rapidly. No displaceable binding is observed in self-block studies. Whole-body PET in humans resulted in effective dose of 29.4 ± 0.6 µSv/MBq with gall bladder, intestines and urinary bladder as organs of highest radioactivity exposure.
Conclusions MK-6240 is a novel, potent and selective ligand for NFTs. [18F]MK-6240 displays favorable brain kinetics in monkey. The effective dose in humans is low in the range of 18F-labeled ligands and further evaluation in AD patients is on-going. Initial brain scans will be presented.