Molecular imaging of rheumatoid arthritis: emerging markers, tools, and techniques.
Bottom Line: Molecular imaging might facilitate more effective diagnosis and monitoring in addition to providing new information on the disease pathogenesis.A limiting factor in the development of new molecular imaging techniques is the availability of suitable probes.In addition, we discuss a new tool that is being introduced in the field, namely the use of nanobodies as tracers.
Early diagnosis and effective monitoring of rheumatoid arthritis (RA) are important for a positive outcome. Instant treatment often results in faster reduction of inflammation and, as a consequence, less structural damage. Anatomical imaging techniques have been in use for a long time, facilitating diagnosis and monitoring of RA. However, mere imaging of anatomical structures provides little information on the processes preceding changes in synovial tissue, cartilage, and bone. Molecular imaging might facilitate more effective diagnosis and monitoring in addition to providing new information on the disease pathogenesis. A limiting factor in the development of new molecular imaging techniques is the availability of suitable probes. Here, we review which cells and molecules can be targeted in the RA joint and discuss the advances that have been made in imaging of arthritis with a focus on such molecular targets as folate receptor, F4/80, macrophage mannose receptor, E-selectin, intercellular adhesion molecule-1, phosphatidylserine, and matrix metalloproteinases. In addition, we discuss a new tool that is being introduced in the field, namely the use of nanobodies as tracers. Finally, we describe additional molecules displaying specific features in joint inflammation and propose these as potential new molecular imaging targets, more specifically receptor activator of nuclear factor κB and its ligand, chemokine receptors, vascular cell adhesion molecule-1, αVβ₃ integrin, P2X7 receptor, suppression of tumorigenicity 2, dendritic cell-specific transmembrane protein, and osteoclast-stimulatory transmembrane protein.
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Mentions: Molecular imaging probes should hold some key properties (that is, rapid binding with high affinity and specificity for the target, rapid clearance of unbound molecules, high target-to-background ratio, high stability, low immunogenicity and toxicity, and feasibility with respect to production and cost). Probes can be constructed from small molecules, peptides, proteins, antibodies, the antigen-binding region of antibodies (Fab fragments), nanobodies, and nanoparticles (Figure 2). Antibodies are frequently used for specific targeting as they have several advantages over other probes. Generic processes for production of monoclonal antibodies are well established, and monoclonal antibodies are highly specific as they recognize a single molecular epitope. On the downside, antibodies may bind non-specifically via their Fc domains. Antibody administration can trigger undesirable anti-immune responses. To increase target specificity and reduce immunogenicity, Fab fragment probes, comprising only one constant and one variable domain of the heavy and light chains, can be used instead of the complete antibody (Figure 2). An emerging technique in molecular imaging is the use of nanobodies (that is, functional variable fragments of single-chain antibodies that are produced by camelids) (Figure 2). The single-variable domain can be cloned relatively easily from lymphocytes of immunized animals. Nanobodies possess full antigen-binding capacity and are very stable . Their small size (15 kDa) enables them to reach epitopes that are shielded for larger antibodies and additionally allows rapid clearance of unbound tracer from the body. Nanobodies can easily be formatted to meet the needs of several applications . For SPECT imaging, their high intrinsic thermostability and carboxy-terminal hexahistidine tail allow straightforward 99mTc-labeling using tricarbonyl chemistry [24,25]. In addition, nanobodies have been validated as tracers for other imaging modalities (for example, NIR-labeled nanobodies for optical imaging  and nanobody-coupled microbubbles for ultrasound ). Imaging with labeled nanobodies has proven its value in preclinical models for atherosclerosis and tumors. SPECT imaging with 99mTc-labeled nanobodies targeting vascular cell adhesion molecule-1 (VCAM-1) in apolipoprotein E-deficient mice identified aortic arch atherosclerotic lesions . Nanobodies against the macrophage mannose receptor (MMR) (CD206) were successfully used in SPECT imaging to specifically visualize a subpopulation of tumor-infiltrating macrophages in mammary adenocarcinoma and Lewis lung carcinoma models in mice .