Evaluation of [¹⁸F]JNJ-CSF1R-1 as a Positron Emission Tomography Ligand Targeting Colony-Stimulating Factor 1 Receptor.

IF 3 4区医学 Q2 RADIOLOGY, NUCLEAR MEDICINE & MEDICAL IMAGING Molecular Imaging and Biology Pub Date : 2025-02-26 DOI:10.1007/s11307-025-01991-9

Mani Salarian, Shuanglong Liu, Hsiu-Ming Tsai, Shannon N Leslie, Thomas Hayes, Su-Tang Lo, Anna K Szardenings, Wei Zhang, Gang Chen, Christine Sandiego, Lisa Wells, Dileep G Nair, Hartmuth C Kolb, Chunfang A Xia

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引用次数: 0

Abstract

Purpose: Colony-stimulating factor 1 receptor (CSF1R) signaling plays a pivotal role in neuroinflammation, driving microglia proliferation and activation. CSF1R is considered a hallmark of inflammation in many neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD). Our study aims to evaluate the potential value of 5-cyano-N-(4-(4-(2-([¹⁸F]fluoro)ethyl)piperazin-1-yl)-2-(piperidin-1-yl)phenyl)furan-2-carboxamide ([¹⁸F]JNJ-CSF1R-1) as a positron emission tomography (PET) ligand targeting CSF1R in preclinical models of neuroinflammation.

Procedures: A cell-based MSD assay was used to measure the IC₅₀ of 5-cyano-N-(4-(4-(2-(fluoro)ethyl)piperazin-1-yl)-2-(piperidin-1-yl)phenyl)furan-2-carboxamide (JNJ-CSF1R-1). JNJ-CSF1R-1 was radiolabeled with fluorine-18. PET imaging was used to evaluate brain uptake, and target engagement of [¹⁸F]JNJ-CSF1R-1 in two neuroinflammation mouse models, including systemic lipopolysaccharide (LPS) and App^SAA knock in (KI). CSF1R protein levels in brain tissue were determined by western blot and ELISA assays. [¹⁸F]JNJ-CSF1R-1 brain uptake was also measured in a non-human primate (NHP) PET study.

Results: JNJ-CSF1R-1 is a 12 nM (IC₅₀) inhibitor of CSF1R. [¹⁸F]JNJ-CSF1R-1 demonstrated significantly higher brain uptake in both LPS and AD mouse models as measured by the area under the time activity curves (AUC) compared to control animals. In the App^SAA KI model, CSF1R levels increased near amyloid plaques as detected by IHC. [¹⁸F]JNJ-CSF1R-1 PET imaging signal showed a good correlation with CSF1R expression levels measured by western blot and ELISA. In an NHP study, [¹⁸F]JNJ-CSF1R-1 readily entered the brain and demonstrated reversible kinetics.

Conclusion: [¹⁸F]JNJ-CSF1R-1 is a potent and promising CSF1R PET tracer with translational potential for measuring microglia-based neuroinflammatory processes and for tracking the impact of anti-inflammatory therapies.

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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.