JNJ-64326067

JNJ-64326067 is a blood-brain barrier-penetrant ligand for aggregated tau protein with a Ki of 2.4 nM. It selectively binds to aggregated tau protein without interacting with aggregated β-amyloid and exhibits no significant off-target binding to tested receptors, ion channels, transporters, kinases, or monoamine oxidases. JNJ-64326067 is useful for Alzheimer's disease research.

[3 H]JNJ-64326067 and [18 F]JNJ-64326067 specifically bind to tau pathology in postmortem human AD (Alzheimer's Disease) brain slices, without binding to pathology where only Aβ (amyloid-beta) is present. This binding is selectively blocked by non-radioactive JNJ-64326067. JNJ-64326067 has physicochemical properties suitable for penetrating the central nervous system, exhibits no significant MDR1-mediated efflux, has a low free fraction in plasma and brain tissue, and shows a high intrinsic clearance rate in rat, monkey, and human liver microsomes and hepatocytes.

In healthy male Sprague-Dawley rats, JNJ-64326067 (0.03 mg/kg; intravenous injection; single dose) demonstrates a rapid plasma clearance rate, a short plasma half-life, and good brain exposure levels, with a cortex-to-plasma ratio of 4.0. In healthy female Wistar rats, JNJ-64326067 (1-10 mg/kg; subcutaneous injection; intravenous injection; single dose) shows a high initial brain uptake rate, rapid clearance, and no off-target binding; bone uptake indicates defluorination in vivo. In healthy male rhesus monkeys, JNJ-64326067 (1 mg/kg; intravenous injection; single dose; co-injected with [18 F]9) displays high brain uptake, rapid clearance, uniform brain distribution, and no bone uptake. Blockade studies indicate an increased peak uptake due to enhanced tracer availability in the brain.