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Purpose <p>The AMPA receptor (AMPARs) mediates fast excitatory neurotransmission and is the central to synaptic plasticity, learning and memory dysregulation of this system has been implicated in epilepsy, neurodegeneration, and neuropsychiatric disorders. The transmembrane AMPA receptor regulatory protein γ8 (TARP γ8) plays a crucial role in the expression and localization of AMPARs within the brain, particularly in the hippocampus and cortex. A selective positron emission tomography (PET) ligand to image this target is of significant interest for investigating potential clinical AMPAR/TARP γ8 antagonists. This study describes the development and preclinical evaluation of a potent and selective tracer targeting TARP γ8, [<sup>18</sup>F]JNJ-1.</p> Procedures <p>The binding potency of JNJ-1 was evaluated using a calcium flux assay in HEK-293 cells. The radiotracer was synthesized on an automated synthesizer via a one-step substitution. TARP γ8 target expression in brains was confirmed through immunohistochemistry (IHC), and adjacent brain sections were used for autoradiography (ARG). In vivo assays were conducted in rats, knockout mice, and non-human primates by [<sup>18</sup>F]JNJ-1 PET imaging and JNJ-1 microdosing studies.</p> Results <p>JNJ-1 exhibited very high binding potency to TARP γ8, IC<sub>50</sub> = 50 pM. Immunoreactivity of TARP γ8 showed high intensity in the hippocampus and moderate levels in the cortex across mouse, rat, and monkey brains. A microdosing with JNJ-1 study revealed high, moderate, and low levels of JNJ-1 uptake in the hippocampus, cortex, and cerebellum, respectively in wild-type mice (γ8 + / +), and low levels in all regions in knockout (γ8 − / −) mouse brains. In vitro ARG of [<sup>18</sup>F]JNJ-1 corresponded with IHC staining on adjacent rat brain sections, and the signal being blocked by JNJ-2, a potent and selective antagonist of TARP γ8. In vivo PET imaging demonstrated high brain uptake in the expected areas in rats and monkeys, which was blockable by JNJ-2 in a dose-dependent manner.</p> Conclusion <p>[<sup>18</sup>F]JNJ-1 is emerging as a promising PET tracer with high in vitro binding affinity and evidence suggestive of target engagement at AMPAR/TARP γ8. The process of clinical validation is presently underway.</p>

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Preclinical Evaluation of [18F]JNJ-1: A Novel Positron Emission Tomography Ligand Targeting AMPAR/TARP γ8

  • 期刊论文

  • 发表日期：

    2026年6月15日

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  • Chunfang A. Xia,
  • Wei Zhang,
  • Tamara Berdyyeva,
  • Chaofeng Huang,
  • Michael K. Ameriks,
  • Terry P. Lebold,
  • Michael P. Maher,
  • Cristian C. Constantinescu,
  • Leslie Nguyen,
  • Nyantsz Wu,
  • Gang Chen,
  • Hartmuth C. Kolb,
  • Anna Katrin Szardenings

摘要

Purpose

The AMPA receptor (AMPARs) mediates fast excitatory neurotransmission and is the central to synaptic plasticity, learning and memory dysregulation of this system has been implicated in epilepsy, neurodegeneration, and neuropsychiatric disorders. The transmembrane AMPA receptor regulatory protein γ8 (TARP γ8) plays a crucial role in the expression and localization of AMPARs within the brain, particularly in the hippocampus and cortex. A selective positron emission tomography (PET) ligand to image this target is of significant interest for investigating potential clinical AMPAR/TARP γ8 antagonists. This study describes the development and preclinical evaluation of a potent and selective tracer targeting TARP γ8, [18F]JNJ-1.

Procedures

The binding potency of JNJ-1 was evaluated using a calcium flux assay in HEK-293 cells. The radiotracer was synthesized on an automated synthesizer via a one-step substitution. TARP γ8 target expression in brains was confirmed through immunohistochemistry (IHC), and adjacent brain sections were used for autoradiography (ARG). In vivo assays were conducted in rats, knockout mice, and non-human primates by [18F]JNJ-1 PET imaging and JNJ-1 microdosing studies.

Results

JNJ-1 exhibited very high binding potency to TARP γ8, IC50 = 50 pM. Immunoreactivity of TARP γ8 showed high intensity in the hippocampus and moderate levels in the cortex across mouse, rat, and monkey brains. A microdosing with JNJ-1 study revealed high, moderate, and low levels of JNJ-1 uptake in the hippocampus, cortex, and cerebellum, respectively in wild-type mice (γ8 + / +), and low levels in all regions in knockout (γ8 − / −) mouse brains. In vitro ARG of [18F]JNJ-1 corresponded with IHC staining on adjacent rat brain sections, and the signal being blocked by JNJ-2, a potent and selective antagonist of TARP γ8. In vivo PET imaging demonstrated high brain uptake in the expected areas in rats and monkeys, which was blockable by JNJ-2 in a dose-dependent manner.

Conclusion

[18F]JNJ-1 is emerging as a promising PET tracer with high in vitro binding affinity and evidence suggestive of target engagement at AMPAR/TARP γ8. The process of clinical validation is presently underway.