PET imaging agents targeting macrophage surface receptors

Abstract

Inflammation is a defense reaction produced by the body to protect against pathogenic factors, whereas the persistent state of inflammation or excessive inflammatory response is the pathological basis of many afflictions. As the main type of activated inflammatory cells in the inflammatory environment, macrophages exert great influence on the outcome of inflammation. For example, “M1” macrophages play a role in promoting inflammation and inhibiting cell proliferation, while “M2” macrophages have an anti-inflammatory effect, promoting cell proliferation and tissue repair. Therefore, correctly identifying macrophage subtypes can help clinical diagnosis and treatment. Positron emission tomography (PET) imaging can be used to recognize macrophages in vivo at the molecular level using various positron nuclides called markers, thereby enabling early diagnosis, prognostic evaluation, and therapeutic efficacy judgment of inflammatory diseases, as well as the development of possible treatment plans. Currently, PET imaging agents that target macrophages can be roughly classified into metabolic, enzyme, cytokine, and receptor imaging agents. However, the first three types of imaging agents have not shown good macrophage specificity and have certain limitations in distinguishing macrophage subtypes. Take metabolic imaging agents, 18F-FDG, as an example. Although activated macrophage cells present high uptake of 18F-FDG, 18F-FDG is still not a specific macrophages-target imaging agent, as its uptake is high in many activated immune cells and other proliferating cell resulting in high non-specific background radioactivity and dramatically lower the diagnostic accuracy. Besides, 18F-FDG, as a non-specific imaging agent, is oftentimes influenced by varying conditions, thereby producing false positive results when used for inflammatory cell imaging. Thus, there is a need to develop specific agents for inflammation imaging. Since macrophages have many characteristic proteins on their surface, different macrophage subtypes exhibit characteristic protein expression. Therefore, the development of radioactive molecular probes for these characteristic receptor proteins will benefit macrophage-specific imaging. Transporter-18 kD (TSPO) is currently the most widely studied macrophage-specific imaging target. However, due to the genetic polymorphism of TSPO, different TSPO PET imaging agents exhibit different TSPO binding affinities. In addition, regardless of macrophages’ polarization (pro- or anti-inflammatory state), activated macrophages display similar TSPO expression. These shortcomings limit the potential interest in TSPO. However, limitations of the TSPO have led to the identification of other molecular targets to develop new tracers of activated macrophages, and there are a lot of specific receptors have been proposed so far. Therefore, in this review, we survey alternative biological targets of recent interest in macrophage activation imaging, including purinergic receptor P2X7, cannabinoid receptors, chemokine receptors, folate receptor β, mannose receptors, adenosine 2A receptor, and others, and examine the potential of these imaging molecular targets in the activation of macrophage expression. In addition, we describe promising PET imaging agents for these targets.