⁶⁸Ga-Labeled Dimeric Cyclic Peptide for Nectin-4-Targeted PET Imaging: From Preclinical Evaluation to First-in-Human Imaging in Breast Cancer.

Authors

Shushan Ge, Jihui Li, Jinyu Shi, Tongtong Jia, Dingding Ai, Junpeng Li, Shibiao Sang, Jing Lan, Bin Zhang, Shengming Deng

Published in

Journal of nuclear medicine : official publication, Society of Nuclear Medicine. Oct 08, 2026. Epub Oct 08, 2026.

Abstract

Nectin-4 is an attractive target for molecular imaging and targeted therapy because of its overexpression in multiple malignancies. We developed a nectin cell adhesion molecule 4 (nectin-4)-targeted ⁶⁸Ga-labeled dimeric cyclic peptide PET tracer, [⁶⁸Ga]Ga-TDN1, for noninvasive imaging of nectin-4 expression. Methods: TDN1 was generated by click chemistry to conjugate 2 nectin-4-binding bicyclic peptides and was radiolabeled with ⁶⁸Ga. Binding affinity was assessed by surface plasmon resonance. Target specificity and tumor-targeting ability were evaluated by cell uptake, blocking, small-animal PET/CT, and biodistribution studies in nectin-4-positive and nectin-4-negative tumor models. [⁶⁸Ga]Ga-TDN1 was further compared with [⁶⁸Ga]Ga-N188 in preclinical models. After preclinical evaluation, [⁶⁸Ga]Ga-TDN1 PET/CT was investigated in a pilot first-in-human study in 6 patients with breast cancer and directly compared with [¹⁸F]FDG PET/CT. Results: TDN1 showed high affinity for nectin-4 (K _D = 1.92 × 10^-10 M). In preclinical studies, [⁶⁸Ga]Ga-TDN1 showed specific uptake in nectin-4-positive cells and tumors, low uptake in nectin-4-negative models, and marked reduction in uptake under blocking conditions. Compared with [⁶⁸Ga]Ga-N188, [⁶⁸Ga]Ga-TDN1 showed higher tumor uptake and longer retention across multiple nectin-4-positive xenografts. In the pilot clinical study, [⁶⁸Ga]Ga-TDN1 was well-tolerated and showed favorable biodistribution and dosimetry. [⁶⁸Ga]Ga-TDN1 PET/CT revealed imaging performance comparable to that of [¹⁸F]FDG PET/CT for primary tumors and most nodal metastases and demonstrated higher uptake and improved lesion detection in bone and liver metastases in selected patients. [⁶⁸Ga]Ga-TDN1 was a clinically translatable nectin-4-targeted PET tracer with high affinity, favorable pharmacokinetics, and specific tumor uptake. Preclinical and pilot clinical results supported further clinical evaluation of [⁶⁸Ga]Ga-TDN1 for noninvasive imaging of nectin-4 expression, particularly for assessment of metastatic disease.

PMID:
42850038
Bibliographic data and abstract were imported from PubMed on 09 Oct 2026.

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