4.1.2. Intercellular Adhesion Molecule-1 (ICAM-1, CD54)-Targeting Probes

ICAM-1, belonging to the immunoglobulin superfamily of cell adhesion molecules, consists of five extracellular IgG-like domains and one cytoplasmic tail [115]. ICAM-1 is found to be expressed at low levels in normal tissue, but at high levels in multiple types of cancer, including TCs [116,117]. One of its important features is that it can initiate tumor transmigration and invasion [116,118]. Furthermore, ICAM-1-targeted chimeric antigen receptor T (CAR-T) cells can robustly kill TC cells [119,120]. Research thus far has suggested ICAM-1 as an ideal target for TC diagnosis and treatments. For this purpose, Wei et al. created an immunoPET probe [64Cu]Cu-NOTA-ICAM-1, which targets ICAM-1. [64Cu]Cu-NOTA-ICAM-1 immunoPET imaging showed high contrast in diagnosing the subcutaneous and orthotopic ATCs in preclinical settings [101] (Figure 9). With the published data and unpublished data in hand, we believe that ICAM-1 may serve as a viable biomarker for certain types of TCs. However, it remains to see the diagnostic utility of ICAM-1–targeted tracers in patients with TCs.

4.1.3. Lectin Galactoside-Binding Soluble 3 (LGALS3, Galectin-3, or Gal3)-Targeting Probes

Gal-3 is a protein that is undetectable in normal and benign thyroid tissues but highly expressed in DTC cytosol, cell membranes, and intercellular substance [121]. The expression of galectin-3 as a biomarker for TCs has been validated in two multicenter studies [122,123]. The sensitivity and specificity of Gal-3 immunodetection reached 94% and 98% in distinguishing benign from TC lesions, with positive and negative predictive values of 98% and 94%, respectively, and diagnostic accuracy of 96% [122]. [89Zr]Zr-labeled Gal3 mAb ([89Zr]Zr-DFO-Gal3) or Gal-3 mAb with F(ab')2 conjunction ([89Zr]Zr-Gal3- F(ab')2) has shown good binding to TC in vivo, allowing it to be potentially used for the detection of recurrence and metastases [124,125] (Figure 10). The particular design of [ 89Zr]Zr-DFO-Gal3-F(ab')2, a protein formed of two F(ab') fragments, results in faster blood clearance and lower liver uptake than traditional mAb-based tracers [125]. The high uptake of [89Zr]Zr-DFO-Gal3-F(ab')2 in kidneys is due to the urinary excretion [125], which should not be problematic because metastatic TC to the kidney is very rare [126]. For a diagnostic purpose, the dose is usually quite low and so is the nephrotoxicity. Thus [89Zr]Zr-DFO-

Gal3-F(ab')2 might be an excellent candidate for translation into the preoperative evaluation and postoperative follow-up.

**Figure 9.** [ 64Cu]Cu-NOTA-ICAM-1 immunoPET imaging in ATC xenografts (cell line: THJ-16T). (**A**) Maximum intensity projection (MIP) images in an orthotopic model. (**B**) MIP images in a subcutaneous model. (**C**) Coronal images of the same model. Reproduced with permission from [101], copyright 2020 Springer Nature Inc.

**Figure 10.** Characterization of [89Zr]Zr-Gal-3 in TC xenografts. (**A**) PET image acquired at 48 h post radiotracer injection in a subcutaneous TC model showed an apparent accumulation of [89Zr]Zr-Gal-3 in a tumor at the right thigh; Reproduced with permission from copyright 2016 American Association for Cancer Research [124]. (**B**) TC in an orthotopic model was visualized after injection of Cy5.5-Gal-3 with fluorescence imaging in the neck. Reproduced with permission from [125] copyright 2019 Society of Nuclear Medicine and Molecular Imaging.
