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

IF 2.5 4区医学 Q2 RADIOLOGY, NUCLEAR MEDICINE & MEDICAL IMAGING

Molecular Imaging and Biology Pub Date : 2026-06-15 DOI:10.1007/s11307-026-02112-w

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

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引用次数: 0

Abstract

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.

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靶向AMPAR/TARP γ - 8的新型正电子发射断层成像配体[18F]JNJ-1的临床前评价。

目的：AMPA受体（AMPARs）介导快速兴奋性神经传递，是突触可塑性的核心，该系统的学习和记忆失调与癫痫、神经变性和神经精神疾病有关。跨膜AMPA受体调节蛋白γ - 8 （TARP γ - 8）在脑内，特别是海马和皮层AMPA的表达和定位中起着至关重要的作用。选择性正电子发射断层扫描（PET）配体对该靶标成像对于研究潜在的临床AMPAR/TARP γ - 8拮抗剂具有重要意义。本研究描述了一种靶向TARP γ8， [18F]JNJ-1的强效、选择性示踪剂的开发和临床前评价。方法：采用钙通量法评价JNJ-1在HEK-293细胞中的结合效力。放射性示踪剂是通过一步取代在自动合成器上合成的。通过免疫组化（IHC）证实TARP γ - 8靶蛋白在脑组织中的表达，并采用邻近脑切片进行放射自显影（ARG）。通过[18F]JNJ-1 PET显像和JNJ-1微给药研究，在大鼠、敲除小鼠和非人灵长类动物中进行体内实验。结果：JNJ-1对TARP γ - 8具有很强的结合能力，IC50 = 50 pM。在小鼠、大鼠和猴的大脑中，TARP γ - 8的免疫反应性在海马中表现出高强度，在皮层中表现出中等水平。JNJ-1微剂量研究显示，野生型小鼠（γ8 + / +）海马、皮质和小脑分别有高、中、低水平的JNJ-1摄取，而敲除型小鼠（γ8 - / -）脑的所有区域都有低水平的JNJ-1摄取。[18F]JNJ-1的体外ARG与邻近大鼠脑切片的IHC染色相对应，并且信号被强效和选择性的TARP γ8拮抗剂JNJ-2阻断。体内PET成像显示，在大鼠和猴子的预期区域有高的脑摄取，JNJ-2可以以剂量依赖的方式阻断。结论：[18F]JNJ-1正成为一种有前景的PET示踪剂，具有高的体外结合亲和力，并有证据表明其与AMPAR/TARP γ - 8靶向结合。目前正在进行临床验证。

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来源期刊

Molecular Imaging and Biology 医学-核医学

CiteScore

6.90

自引率

3.20%

发文量

审稿时长

3 months

期刊介绍： Molecular Imaging and Biology (MIB) invites original contributions (research articles, review articles, commentaries, etc.) on the utilization of molecular imaging (i.e., nuclear imaging, optical imaging, autoradiography and pathology, MRI, MPI, ultrasound imaging, radiomics/genomics etc.) to investigate questions related to biology and health. The objective of MIB is to provide a forum to the discovery of molecular mechanisms of disease through the use of imaging techniques. We aim to investigate the biological nature of disease in patients and establish new molecular imaging diagnostic and therapy procedures. Some areas that are covered are: Preclinical and clinical imaging of macromolecular targets (e.g., genes, receptors, enzymes) involved in significant biological processes. The design, characterization, and study of new molecular imaging probes and contrast agents for the functional interrogation of macromolecular targets. Development and evaluation of imaging systems including instrumentation, image reconstruction algorithms, image analysis, and display. Development of molecular assay approaches leading to quantification of the biological information obtained in molecular imaging. Study of in vivo animal models of disease for the development of new molecular diagnostics and therapeutics. Extension of in vitro and in vivo discoveries using disease models, into well designed clinical research investigations. Clinical molecular imaging involving clinical investigations, clinical trials and medical management or cost-effectiveness studies.