68Ga-Labeled TMTP1 Modified with d-Amino Acid for Positron Emission Tomography Diagnosis of Highly Metastatic Hepatocellular Carcinoma

TMTP1 (NVVRQ) has been proven to selectively target various highly metastatic tumor cells. Nonetheless, existing TMTP1 probes encounter challenges such as rapid blood clearance, limited tumor uptake, and inadequate suitability for therapeutic interventions. To overcome these constraints, we designed and synthesized eight peptide probes, employing innovative chemical modification strategies involving d-amino acid modification and retro-inverso isomerization. Notably, [⁶⁸Ga]TV₂ exhibited particularly impressive performance, displaying an 88.88, 76.90, and 90.32% improvement in uptake at 15, 30, and 60 min, respectively, while maintaining a high target-to-nontarget ratio. Further research has demonstrated that [⁶⁸Ga]TV₂ also exhibits remarkable diagnostic potential for detecting in situ microtumors in the liver. The results suggest that through the implementation of innovative chemical modification strategies, we successfully developed a peptide precursor, NOTA-G-NVvRQ, with specific affinity for highly metastatic tumors, enhanced in vivo pharmacokinetic profile, and heightened stability in vivo, rendering it well suited for prospective investigations in combination therapy studies.