Positron Emission Tomography (PET) is a noninvasive imaging modality combining anatomical and functional information. In neuroscience, PET imaging provides a powerful tool to support therapeutic translation by measuring central target engagement of a therapeutic compound in the brain. In this presentation, imaging studies for receptor occupancy will be discussed for two targets: P2X7 and AMPA TARP γ8. The P2X7 receptor is an adenosine triphosphate (ATP)-gated ion-channel, which is abundantly expressed in glial cells within the central nervous system. P2X7R activation leads to the release of the pro-inflammatory cytokine IL-1β in the brain and as such the P2X7 receptor may play a role in neuroinflammation. Our novel P2X7R PET tracer, [18F]JNJ-64413739, is a promising candidate for imaging of neuroinflammation in the brain. PET images with [18F]JNJ-64413739 correlated well with other biomarkers of neuroinflammation. In blocking experiments with [18F]JNJ-64413739, tracer brain uptake in NHPs was reduced in a dose-dependent manner by a P2X7R antagonists JNJ-54175446 and receptor occupancies (RO) at different dose levels were calculated. First in-human studies show sufficient brain uptake and like in NHPs, a dose-response relationship with the P2X7 antagonist JNJ-54175446. The transmembrane receptor regulatory protein TARP γ8, which is preferentially expressed in the hippocampus, controls hippocampal AMPA receptor expression, distribution and synaptic plasticity. A novel AMPA TARP γ8 PET tracer, [18F]JNJ-64511070, has been developed and evaluated by in vivo imaging in NHPs in the absence and presence of JNJ-64140284, a selective AMPAR/γ8 antagonist. A Phase 0 exploratory study of [18F]JNJ-64511070 was initiated to evaluate the safety of the tracer and to visually and quantitatively assess brain uptake and pharmacokinetics of [18F]JNJ-64511070 in healthy subjects. The initial clinical evaluation of [18F]JNJ-64511070 suggests that this tracer is a suitable candidate PET ligand for imaging AMPAR/γ8 TARP and supporting its use for clinical target engagement studies.

PET imaging strategies for measurement of target engagement

ACS Fall 2020 Virtual Meeting

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