Development and Evaluation of 68Ga-Labeled TMTP1-Based Cyclic Peptide Probes for Targeting Hepatocellular Carcinoma.

Abstract

This study focused on the development and evaluation of four [⁶⁸Ga]-labeled cyclic TMTP1 peptide-based probes for targeting highly metastatic hepatocellular carcinoma (HCC). The probes─[⁶⁸Ga]Ga-N-G-NVvRQ, [⁶⁸Ga]Ga-c[K(N)NVvRQ], [⁶⁸Ga]Ga-c[K(N)NVVRQ], and [⁶⁸Ga]Ga-c[K(N)NVvRQ]₂─were designed using a head-to-tail cyclization strategy to enhance their stability, improve tumor targeting, and reduce uptake in nontarget organs. The microPET imaging results showed that although tumor uptake for all four probes was similar at each time point, renal evaluation revealed that [⁶⁸Ga]Ga-c[K(N)NVvRQ] had the lowest value at 15 min (1.90 ± 0.87%ID/g), significantly outperforming linear analog [⁶⁸Ga]Ga-N-G-NVvRQ (2.87 ± 0.86%ID/g) and dimeric peptide, [⁶⁸Ga]Ga-c[K(N)NVvRQ]₂ (3.92 ± 0.68%ID/g), and the probe exhibited the lowest physiological uptake across major organs. At 30 min, the liver uptake of [⁶⁸Ga]Ga-c[K(N)NVvRQ] was 0.29 ± 0.08%ID/g, with a tumor-to-liver (T/L) ratio of 2.45 ± 0.03. This low nonspecific uptake in normal organs contributed to high-contrast PET imaging, facilitating the diagnosis of small tumor lesions. In addition, the probe demonstrated sustained low renal radioactivity retention, which may offer potential benefits for minimizing additional radioactive damage to the kidneys. Overall, [⁶⁸Ga]Ga-c[K(N)NVvRQ] achieved a good balance between strong tumor uptake and low nonspecific uptake in organs (especially in kidneys), making it an ideal candidate for further investigation in HCC imaging applications.