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. 2025 Sep;52(11):4078-4091.
doi: 10.1007/s00259-025-07286-z. Epub 2025 Apr 21.

Development and clinical evaluation of [68Ga]Ga-NODAGA-ADAPT6 as a novel HER2-targeted PET radiotracer for breast cancer imaging and treatment monitoring

Weijing Tao #  1 , Jinglin Zhang #  2 , Xin Meng #  3 , Xuedong Han #  4 , Qiuhu Wang  5 , Yixiang Lin  2 , Luyi Cheng  5 , Minmin Liu  4 , Dongzhu Da  4 , Huai Zhang  5 , Junfu Fan  5 , Lianmei Zhang  6 , Shuangyue Liu  4 , Shuo Li  4 , Feng Gao  7 , Yi Ren  8   9
Affiliations

Development and clinical evaluation of [68Ga]Ga-NODAGA-ADAPT6 as a novel HER2-targeted PET radiotracer for breast cancer imaging and treatment monitoring

Weijing Tao et al. Eur J Nucl Med Mol Imaging. 2025 Sep.

Abstract

Purpose: Accurate assessment of human epidermal growth factor receptor type 2 (HER2) expression is crucial for diagnosis, treatment planning, and monitoring of breast cancer patients. A 68Ga-labeled tracer based on the albumin-binding domain-derived affinity protein 6 (ADAPT6) was developed to evaluate HER2 expression in breast cancer.

Methods: The gene encoding ADAPT6 was modified with N-terminal (GHEHEHEDANS) and C-terminal (GSSC) extensions to enhance its functionality. The precursor was synthesized, purified, and characterized, followed by radiolabeling with 68Ga to produce [68Ga]Ga-NODAGA-ADAPT6. In vivo metabolism and biodistribution studies were performed in HCC1954 (HER2-positive) and MDA-MB-468 (HER2-negative) tumor-bearing mice. Additionally, with ethical approval and informed consent, 22 breast cancer patients underwent [68Ga]Ga-NODAGA-ADAPT6 PET imaging to assess HER2 expression in primary and metastatic lesions.

Results: The tracer was prepared with a radiochemical purity exceeding 99% and demonstrated high stability in vivo. Micro-PET/CT imaging revealed significant accumulation of the radiotracer in HCC1954 tumors, which was markedly reduced after HER2 blockade with trastuzumab. In contrast, MDA-MB-468 tumors showed minimal uptake. In the clinical study, [68Ga]Ga-NODAGA-ADAPT6 PET images displayed varying levels of radiotracer uptake in primary and metastatic lesions, which correlated well with the HER2 expression status determined by pathological analysis.

Conclusion: [68Ga]Ga-NODAGA-ADAPT6 exhibited excellent pharmacokinetic properties and high specificity for HER2-expressing lesions in PET imaging. These findings highlight its potential as a promising tool for distinguishing different levels of HER2 expression in breast cancer, aiding in personalized treatment strategies.

Keywords: 68Ga; ADAPT6; Breast cancer; HER2; Positron emission tomography (PET).

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Conflict of interest statement

Declarations. Ethics approval: Animal experiments were conducted following the regulations approved by the Animal Ethics Committee of Shandong University (ECSBMSSDU2021-2-24). Human studies were approved by the Ethics Committee of Huai’an First People’s Hospital (Approval No. KY-2023-09-01). Consent to participate: Informed consent was obtained from all individual participants included in the study. Competing interests: All authors declare they have no relevant financial or non-financial interests that are directly or indirectly related to the work submitted for publication. Trial registration: The clinical evaluation of this study was registered On October 25, 2024 at https://www.chictr.org.cn/ (No: ChiCTR2400091303).

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