JNJ-64326067 is an aggregated tau-binding agent with blood-brain barrier permeability, with a K i of 2.4 nM. JNJ-64326067 selectively binds to aggregated tau protein but does not bind to aggregated β-amyloid protein, and shows no significant off-target binding to the tested receptors, ion channels, transporters, kinases or monoamine oxidases. JNJ-64326067 is applicable to the research of Alzheimer's disease [1].
In Vivo, JNJ-64326067 (0.03 mg/kg; i.v.; single dose) exhibits fast plasma clearance, short plasma half-life, and good brain exposure in healthy male Sprague-Dawley rats, with a cortex-to-plasma ratio of 4.0[1]. JNJ-64326067 (1-10 mg/kg; s.c.; i.v.; single dose) shows high initial brain uptake, rapid washout, and no detectable off-target binding in healthy female Wistar rats, with bone uptake indicating in vivo defluorination[1]. JNJ-64326067 (1 mg/kg; i.v.; single dose; simultaneous with [18F]9 injection) exhibits high brain uptake, rapid washout, homogeneous brain distribution, and no bone uptake in healthy male rhesus monkeys, with a blocking study showing increased peak uptake due to enhanced tracer availability for brain entry[1].
In Vitro, [3H]JNJ-64326067 and [18F]JNJ-64326067 specifically bind to tau pathologies in post-mortem human AD brain sections, but do not bind to pathologies with only Aβ present, and this binding can be selectively blocked by non-radioactive JNJ-64326067[1]. JNJ-64326067 possesses physicochemical properties suitable for central nervous system penetration, exhibits no significant MDR1-mediated efflux, has a low free fraction in plasma and brain tissue, and shows high intrinsic clearance in rat, monkey and human liver microsomes as well as hepatocytes[1].
References:
[1]. Rombouts FJR, et al. Discovery of N-(4-[ 18 F]Fluoro-5-methylpyridin-2-yl)isoquinolin-6-amine (JNJ-64326067), a New Promising Tau Positron Emission Tomography Imaging Tracer. J Med Chem. 2019;62(6):2974-2987.
In Vivo, JNJ-64326067 (0.03 mg/kg; i.v.; single dose) exhibits fast plasma clearance, short plasma half-life, and good brain exposure in healthy male Sprague-Dawley rats, with a cortex-to-plasma ratio of 4.0[1]. JNJ-64326067 (1-10 mg/kg; s.c.; i.v.; single dose) shows high initial brain uptake, rapid washout, and no detectable off-target binding in healthy female Wistar rats, with bone uptake indicating in vivo defluorination[1]. JNJ-64326067 (1 mg/kg; i.v.; single dose; simultaneous with [18F]9 injection) exhibits high brain uptake, rapid washout, homogeneous brain distribution, and no bone uptake in healthy male rhesus monkeys, with a blocking study showing increased peak uptake due to enhanced tracer availability for brain entry[1].
In Vitro, [3H]JNJ-64326067 and [18F]JNJ-64326067 specifically bind to tau pathologies in post-mortem human AD brain sections, but do not bind to pathologies with only Aβ present, and this binding can be selectively blocked by non-radioactive JNJ-64326067[1]. JNJ-64326067 possesses physicochemical properties suitable for central nervous system penetration, exhibits no significant MDR1-mediated efflux, has a low free fraction in plasma and brain tissue, and shows high intrinsic clearance in rat, monkey and human liver microsomes as well as hepatocytes[1].
References:
[1]. Rombouts FJR, et al. Discovery of N-(4-[ 18 F]Fluoro-5-methylpyridin-2-yl)isoquinolin-6-amine (JNJ-64326067), a New Promising Tau Positron Emission Tomography Imaging Tracer. J Med Chem. 2019;62(6):2974-2987.