10 Chapter 1 Larger molecules such as monoclonal antibodies have been used for molecular imaging because of their high specificity and binding affinity towards the target. Additionally, the biodistribution of the antibody can be visualized, and provides the most robust biomarker to correlate tracer uptake or tumor dosing, with treatment response. Their longer half-life requires a longer-lived radionuclides such as zirconium-89 (78.4 hours)15. Zirconium-89 is the radionuclide of preference of imaging with monoclonal antibodies because it remains in cells after internalization of the antibody-receptor complex, resulting in an improved tumor image contrast via accumulation. Additionally, zirconium-89 is a positron-emitting radionuclide and thus suitable for PET imaging, which has improved resolution and quantification compared to Single photon-emission computed tomography (SPECT)16. When radiolabeled, a so-called radiotracer can be visualized by detecting the emitted gamma rays by SPECT or PET-imaging. The result in a whole-body 3-dimensional reconstruction of the distribution of the tracer. The process is depicted in Figure 1. Figure 1. Molecular PET-imaging with radiolabeled antibodies. A monoclonal antibody (1) is radiolabeled to a radionuclide to form a radiotracer (2). This radiotracer is then administered to a patient with e.g., a lung tumor with target expression. Depended on the radionuclide of choice, SPECT or PET-imaging is performed to detect the emitted gamma rays (3). After reconstruction, the radiotracer can be localized at the site of target expression (4). Compared to SPECT, PET has superior resolution and sensitivity, enabling the detection of smaller lesions (±10mm) and accurate quantification. In combination with conventional imaging modalities such as CT and MRI for anatomical reference, tumor lesions can be located, and tracer-uptake can be used to study the biological differences between/within tumor lesions. Combined PET/CT or PET/MRI provides both anatomical and functional/biological information. Currently, the most common used radiotracer is [18F]FDG, which discriminates malignant tissue from benign tissue based on metabolic activity. However, the use of PET is rapidly expanding to other applications to gain non-invasive insight in tumor biology and support drug development. Imaging can be used to visualize different tumor features, such as the expression of tumor cell receptors, tumor-associated antigens, metabolic substrates and immune cells. For example, [89Zr]Zr-girentuximab, antibody targeting carbonic anhydrase IX (CAIX) which is over-expressed in clear cell renal cell carcinomas (ccRCC), can be used to visualize CAIX-expressing ccRCC tumor lesions17. Another application of molecular imaging is the visualization of the in vivo distribution,
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