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Mesothelin is a cell-surface glycoprotein restricted to mesothelial cells overexpressed in several types of cancer, including triple-negative breast cancer not responding to trastuzumab or hormone-based therapies. Mesothelin-targeting therapies are currently being developed. However, the identification of patients potentially eligible for such a therapeutic strategy remains challenging. The objective of this study was to perform the radiolabeling and preclinical evaluation of 99m Tc-A1 and 99m Tc-C6, two antimesothelin single-domain antibody (sdAb)-derived imaging agents. Methods: A1 and C6 were radiolabeled with 99m Tc and evaluated in vitro on recombinant protein and cells, as well as in vivo in xenograft mouse models of the triple-negative breast cancer cell lines HCC70 (mesothelin-positive) and MDA-MB-231 (mesothelin-negative). Results: Both 99m Tc-A1 and 99m Tc-C6 bound mesothelin with high affinity in vitro, with 99m Tc-A1 affinity being 2.4-fold higher than that of 99m Tc-C6 (dissociation constant, 43.9 ± 4.0 vs. 107 ± 16 nM, P &lt; 0.05). 99m Tc-A1 and 99m Tc-C6 remained stable in vivo in murine blood (&gt;80% at 2 h) and ex vivo in human blood (&gt;90% at 6 h). In vivo 99m Tc-A1 uptake (percentage injected dose) in HCC70 tumors was 5-fold higher than in MDA-MB-231 tumors and 1.5-fold higher than that of 99m Tc-C6 (2.34% ± 0.36% vs. 0.48% ± 0.18% and 1.56% ± 0.43%, respectively, P &lt; 0.01) and resulted in elevated tumor-to-background ratios. In vivo competition experiments demonstrated the specificity of 99m Tc-A1 uptake in HCC70 tumors. Conclusion: Mesothelin-positive tumors were successfully identified by SPECT using 99m Tc-A1 and 99m Tc-C6. Considering its superior characteristics, 99m Tc-A1 was selected as the most suitable tool for further clinical translation.

Preclinical Evaluation of Mesothelin-Specific Ligands for SPECT Imaging of Triple-Negative Breast Cancer