RT Journal Article SR Electronic T1 Pilot Study of Nectin-4–Targeted PET Imaging Agent 68Ga-FZ-NR-1 in Triple-Negative Breast Cancer from Bench to First-in-Human JF Journal of Nuclear Medicine JO J Nucl Med FD Society of Nuclear Medicine SP jnumed.124.269024 DO 10.2967/jnumed.124.269024 A1 Sun, Li A1 Sun, Yuyun A1 Zuo, Ke A1 Fan, Lei A1 Wang, Xiao A1 Zhang, Jianping A1 Hu, Silong A1 Liu, Xiaosheng A1 Li, Jindian A1 Li, Ye A1 Shao, Zhiming A1 Xu, Xiaoping A1 Wu, Aiguo A1 Song, Shaoli YR 2025 UL http://jnm.snmjournals.org/content/early/2025/02/13/jnumed.124.269024.abstract AB Nectin cell adhesion molecule 4 (Nectin-4) is an emerging biomarker for cancer diagnosis and therapy. We developed a Nectin-4–targeted 68Ga-DOTA-Sar10-Nectin-4 (68Ga-FZ-NR-1) PET/CT radiotracer for detecting Nectin-4 expression in a tumor model and in triple-negative breast cancer (TNBC) patients. Methods: A series of Nectin-4–targeted radiotracers—68Ga-FZ-NR-1, 68Ga-DOTA-polyethylene glycol 5-Nectin-4 (68Ga-FZ-NR-2), and 68Ga-DOTA-polyethylene glycol 10-Nectin-4 (68Ga-FZ-NR-3)—were synthesized, and their targeting ability and specificity were evaluated in vitro and in vivo. In vitro experiments were performed in the MDA-MB-468 (Nectin-4–positive) and MDA-MB-231 (Nectin-4–negative) cell lines. PET/CT imaging in tumor models was performed to assess the Nectin-4–targeting ability of the radiotracers. After preclinical experiments and screening, the 68Ga-FZ-NR-1 radiotracer was selected for safety and efficacy evaluation in a first-in-human trial in TNBC patients. Positive lesions were biopsied and analyzed by immunohistochemistry to determine Nectin-4 expression levels. Results: The 3 68Ga-labeled radiotracers exhibited high radiochemical purity, stability, and strong affinity for Nectin-4. In vitro cell uptake studies showed that the radiotracers effectively targeted Nectin-4 in MDA-MB-468 cells, and 68Ga-FZ-NR-1 showed the highest targeting efficacy. In the MDA-MB-468 tumor model, PET/CT imaging showed that 68Ga-FZ-NR-1 was taken up at higher rates than 68Ga-FZ-NR-2 and 68Ga-FZ-NR-3, and it exhibited favorable pharmacokinetics and safety profiles. 68Ga-FZ-NR-1 was thus selected for subsequent clinical trials. 68Ga-FZ-NR-1 PET/CT effectively identified tumors in 9 patients with TNBC, which was confirmed by 18F-FDG PET/CT. Biopsy samples of the tumor lesions revealed that the positive lesions identified by 68Ga-FZ-NR-1 PET/CT corresponded to areas of high Nectin-4 expression. Conclusion: A series of Nectin-4–targeted radiotracers (68Ga-FZ-NR-1, 68Ga-FZ-NR-2, and 68Ga-FZ-NR-3) was developed and evaluated. Preclinical studies demonstrated that 68Ga-FZ-NR-1 can identify tumors with high Nectin-4 expression. In a preliminary clinical study, 68Ga-FZ-NR-1 was used to effectively identify and visualize Nectin-4–expressing tumor lesions in patients with TNBC, which was confirmed by immunohistochemistry. This radiotracer provides a noninvasive approach to the assessment of Nectin-4 and a potential basis for the development of Nectin-4–targeted treatments for TNBC.