Chemokine receptor PET imaging: Bridging molecular insights with clinical applications

Abstract

Chemokine receptors are important components of cellular signaling and play a critical role in directing leukocytes during inflammatory reactions. Their importance extends to numerous pathological processes, including tumor differentiation, angiogenesis, metastasis, and associations with multiple inflammatory disorders. The necessity to monitor the in vivo interactions of cellular chemokine receptors has been driven the recent development of novel positron emission tomography (PET) imaging agents. This imaging modality provides non-invasive localization and quantitation of these receptors that cannot be provided through blood or tissue-based assays. Herein, we provide a review of PET imaging of the chemokine receptors that have been imaged to date, namely CXCR3, CXCR4, CCR2, CCR5, and CMKLR1. The quantification of these receptors can aid in understanding various diseases, including cancer, atherosclerosis, idiopathic pulmonary fibrosis, and acute respiratory distress syndrome. The development of specific radiotracers targeting these receptors will be discussed, including promising results for disease diagnosis and management. However, challenges persist in fully translating these imaging advancements into practical therapeutic applications. Given the success of CXCR4 PET imaging to date, future research should focus on clinical translation of these approaches to understand their role in the management of a wide variety of diseases.

Keywords: Chemokine receptors; Clinical translation; Diagnostic tools; PET imaging; Radiotracer development.

Figure 1.

Representative PET images of [¹⁸F]1. Red arrows indicate uptake in atherosclerotic aorta, while blue arrows indicate uptake in brown adipose tissue (BAT). This research was originally published in the European Journal of Nuclear Medicine and Molecular Imaging (EJNMMI) Research. Alluri, S. R., et al. (2023). “Synthesis and preclinical evaluation of a novel fluorine-18 labeled small-molecule PET radiotracer for imaging of CXCR3 receptor in mouse models of atherosclerosis.” EJNMMI Res 13(1): 67. Copyright © 2023, Springer Nature.

Figure 2.

Chemical structure of [¹⁸F]1. [25]

Figure 3.

Chemical structure of [⁶⁸Ga]pentixafor. [15]

Figure 4.

Chemical structure of [⁶⁸Ga]Ga1 and [⁶⁸Ga]Ga2. [39]

Figure 5.

Synthesis scheme for derivatives 6a-c that yieleded fluoropentoxy derivative [¹⁸F]6b. [51]

Figure 6.

Chemical structures of [64Cu]DOTA-ECL1i.

Figure 7.

Representative PET images of [⁶⁸Ga]DOTA-ECL1i and [⁶⁴Cu]DOTA-ECL1i uptake in CCR2+ tissues in the heart of mice after ischemia-reperfusion injury. This research was originally published in the Journal of Nuclear Medicine. Heo, G. S., et al. “Targeted PET Imaging of Chemokine Receptor 2-Positive Monocytes and Macrophages in the Injured Heart.” J Nucl Med. 62(1): 111–114. Copyright © 2021, the Society of Nuclear Medicine and Molecular Imaging.

Figure 8.

Chemical structure of [⁶⁴Cu]DAPTA-Comb. [15]

Figure 9.

Synthetic scheme of 10%, 25%, 40% [64Cu]DAPTA-Combs. [70]

Figure 10.

Representative PET images following injection of 10%, 25%, and 40% 64Cu-DAPTA-Comb in ApoE^−/− mice showing significant reduction in signal uptake in AAV treated mice compared to wild type. Reprinted (adapted) with permission from Detering L, Abdilla A, Luehmann HP, et al. CC Chemokine Receptor 5 Targeted Nanoparticles Imaging the Progression and Regression of Atherosclerosis Using Positron Emission Tomography/Computed Tomography. Mol Pharm. 2021;18(3):1386–1396. Copyright © 2021, American Chemical Society.

Figure 11.

Chemical structure of [⁶⁴Cu]NODAGA-CG34. [79]

Figure 12.

Representative comparison images of CT, PET/CT, Autoradiography of murine lungs after injection of [⁶⁴Cu]NODAGA-CG34, correlated to Immunohistochemical/Immunofluorescence analysis for CMKLR1 expression. This research was originally published in Proceedings of the National Academy of Sciences. Mannes, P. Z., et al. (2023). “Molecular imaging of chemokine-like receptor 1 (CMKLR1) in experimental acute lung injury.” Proc Natl Acad Sci U S A 120(3): e2216458120. Copyright © 2023 the Author(s).