Discovery of N-(4-[¹⁸F]Fluoro-5-methylpyridin-2-yl)isoquinolin-6-amine (JNJ-64326067), a New Promising Tau Positron Emission Tomography Imaging Tracer

Abstract

In Alzheimer's disease, the density and spread of aggregated tau protein track well with neurodegeneration and cognitive decline, making the imaging of aggregated tau a compelling biomarker. A structure−activity relationship exploration around an isoquinoline hit, followed by an exploration of tolerated fluorination positions, allowed us to identify 9 (JNJ-64326067), a potent and selective binder to aggregated tau with a favorable pharmacokinetic profile and no apparent off-target binding. This was confirmed in rat and monkey positron emission tomography studies using [ 18 F]9.

Clinical evaluation of [18F] JNJ-64326067, a novel candidate PET tracer for the detection of tau pathology in Alzheimer’s disease

“…Clearance from non-target regions was rapid and retention appeared to plateau in regions known to accumulate tau aggregates by 120 min post injection. There was no evidence of bone uptake that had been seen in rat, consistent with the preclinical studies which differentiated metabolism in primates [ 8 ].…”

“…Determination of whether specific retention of [ 18 F] JNJ-64326067 occurred in regions with probable tau pathology relied on reference tissue methods and did not include arterial sampling that would have supported compartmental modeling. The cerebellum has been evaluated extensively as a reference region for tau PET tracers and is supported by the absence of any nonpolar metabolites in preclinical studies [ 8 ]. As a proof-of-concept, we first wanted to see how [ 18 F] JNJ-64326067 performed compared to tau PET tracers that use reference tissue for quantitation of the NFT signal as a readily implemented and tolerated protocol for clinical trials in AD [ 6 , 15 ] while not burdening subjects with invasive sampling.…”

“…In vitro studies used for the selection of JNJ-64326067 demonstrated potent binding to aggregated tau isolated from human AD brain (inhibition constant [Ki] of 2.4 nM) and > 1000-fold selectivity over Aβ. JNJ 64326067 has an experimental Log D of 3.51 at pH 7.4; a low polar surface area of 38 Å 2 ; a plasma protein binding of 93.6%, 97.0%, and 95.4%, respectively, in humans, mice, and rats; and a brain tissue binding of 98.7% [ 8 ]. Information on the radiosynthesis and production results are provided in the supplementary material .…”

“…In vitro, JNJ-64326067 was found to have high affinity for tau aggregates in post-mortem brain tissue from subjects with AD and high selectivity over β-amyloid aggregates. The absence of significant binding to other brain targets was tested by profiling at CEREP laboratories ( https://www.eurofinsdiscoveryservices.com/ ), with additional testing against MAO-A and MAO-B [ 8 ] as these can confound in vivo imaging [ 9 , 10 ]. Metabolism and kinetics of [ 18 F] JNJ-64326067 were also evaluated in preclinical models.…”

“…Displacement of fluorine by glutathione was observed in rat hepatocytes, and a signal in skull was seen in PET studies in rat. Such displacement was negligible in non-human and human hepatocytes, and no significant defluorination was predicted to occur [ 8 ]. We here report the clinical qualification of the ligand in subjects with probable AD and healthy controls including tracer kinetic modeling, biodistribution, and dosimetry.…”