Abstract
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Objectives [11C]JNJ-42491293 is a novel PET tracer for the metabotropic glutamate receptor subtype 2 (mGluR2) targeting an allosteric site as a potential therapeutic mechanism. The mGluR2 is predominantly presynaptic and modulates glutamate release through feedback inhibition. It is involved in numerous brain functions and is a promising target for disorders such as anxiety, schizophrenia and addiction. The safety, biodistribution, dosimetry, and kinetic modeling of [11C]JNJ-42491293 was determined in humans.
Methods Studies were conducted in 20 healthy male subjects (age range 19-35 y). Biodistribution was determined in 3 subjects using dynamic whole-body PET-CT. Dynamic brain scans of 90 minutes were acquired in 17 healthy volunteers using arterial sampling and metabolite determination. Safety and tolerability were assessed.
Results [11C]JNJ-42491293 was readily taken up in the brain, with maximum around 30 minutes and good washout in grey matter, showed relatively uniform cortical activity and high uptake in striatum and cerebellum, consistent with reported distribution of the mGluR2 in human brain. Of note, the tracer appeared to be retained in striate muscle including the heart, consistent with the reported expression profile for mGluR2 outside the CNS. The effective radiation dose was 4.2 microSv/MBq. [11C]JNJ-42491293 dynamic profiles in humans were modeled with a 2 tissue compartment model. Arterial and venous intact tracer fractions were very similar (R2=0.944) with 30% present after 90 minutes. Volume of distribution (VT) was between 3 and 7 ml.cm-3 for cortex, subcortical grey matter and cerebellum. No serious adverse events were encountered.
Conclusions [11C]JNJ-42491293 is a highly promising PET tracer for measuring mGluR2 availability in humans and may be suitable for assessment of occupancy by drug candidates targeting this allosteric site.
Research Support This study was conducted as clinical trial sponsored by Johnson and Johnson, Belgium