Development and preclinical evaluation of a cyclic PET tracer targeting integrin-α6 on colorectal cancer models

[Display omitted] •A cyclic peptide A6P targeting integrin-α6 was developed, which exhibited the potent binding affinity targeted integrin-α6 (Kd = 13.40 ± 3.41 nM).•A promising PET tracer [18F]AlF-NOTA-A6P with high radiochemical yield (RCY: 58.1 ± 4.1 %) was synthesized in a novel cassette-type synthesis module (Mortenon M1).•[18F]AlF-NOTA-A6P has achieved significant improvements in affinity, stability, tumor uptake and retention time over previous tracer [18F]AlF-NOTA-RD2.•Providing a promising non-invasive PET radiotracer for the detection of colorectal cancer. Integrin-α6 is an attractive diagnostic and therapeutic biomarker in cancer, because it is highly expressed in several types of malignancies. Based on our previous findings, we designed a cyclic peptide, NOTA-A6P, to enhancing affinity, tumor uptake and serum stability, and then developed a cyclic radiotracer, [18F]AlF-NOTA-A6P, for the specific detection of early colorectal cancer by PET/CT imaging. [18F] AlF-NOTA-A6P was automatically labeled for colorectal cancer imaging in a novel synthesis module. The affinity, stability, radiochemical yield (RCY), radiochemical purity (RCP), molar activity (Am), and octanol–water partition coefficient of [18F]AlF-NOTA-A6P were investigated. Results demonstrated that the tracer exhibited high serum stability, high RCY (58.1 ± 4.1 %) (undecay-corrected, n = 5) and hydrophilicity. In vivo microPET/CT imaging of LS174T and HT29 xenograft tumor models with high integrin-α6 expression indicated that [18F]AlF-NOTA-A6P exhibited higher tumor uptake and tumor-to-muscle ratio than SW620, which has low integrin-α6 expression. Moreover, the specificity of [18F]AlF-NOTA-A6P for integrin-α6 was confirmed by additional methods, including autoradiography, hematoxylin and eosin staining, and immunohistochemical staining. In conclusion, a cyclic peptide NOTA-A6P targeting integrin-α6 was designed and a promising PET tracer [18F]AlF-NOTA-A6P was synthesized in a novel cassette-type synthesis module. The tracer demonstrated a favorable binding affinity with integrin-α6, stability in human serum and specificity for colorectal cancer xenograft mice. These properties render it a promising non-invasive PET radiotracer for the detection of integrin-α6-overexpressing cancers, including colorectal cancer.