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Objective: Overexpression of human epidermal growth factor receptor-2 (HER2) in breast cancers provides promising opportunities for imaging and targeted therapy. Developing HER2 targeted positron emission tomography (PET) probes might be benefit for management of the disease. Small high-affinity scaffold proteins, affibodies, are ideal vectors for imaging HER2 overexpressed tumors. Despite of the initial success on development of 18 F labeled ZHER 2:342 affibody, the tedious synthesis producers, low yields and unfavorable pharmacokinetics may hinder the clinical use. 68 Ga is an attractive positron emitter for PET imaging. A simple preparation of 68 Ga labeled ZHER 2:342 analog, 68 Ga-NOTA-MAL-Cys-MZHER 2:342 , was reported in the study. The in vivo performances of the tracer for assessing HER2 status in breast cancers were also evaluated., Methods: NOTA-MAL conjugated Cys-MZHER 2:342 was radiolabeled with 68 Ga. The probe was evaluated by in vitro tests including stability and cell binding studies in breast cancer cells with different HER2 levels. In vivo evaluation was performed in mice bearing tumors using microPET imaging and biodistribution experiments. A PET/CT imaging study was initially performed in patients with breast cancers., Results: The tracer was synthesized in a straightforward chelation method with satisfactory non-decay corrected yield (81±5%) and radiochemical purity (>95%). In vivo micro-PET imaging showed that HER2 high levels expressed BT474 xenografts were more clear visualized than HER2 low levels expressed MCF-7 tumors (16.12 ± 2.69 ID%/g vs 1.32 ± 0.19 ID%/g at 1 h post-injection). The outcome was consistent with the immunohistochemical analysis. No significant radioactivity was accumulated in healthy tissues (less than 2% ID/g) except kidneys. In a preliminary clinical study, 68 Ga-NOTA-MAL-Cys-MZHER 2:342 PET imaging allowed more high-contrast detection of HER2 positive primary tumors (maximum standardized uptake value = 2.16±0.27) than those in HER2 negative primary focus (maximum standardized uptake value = 0.32±0.05). No detectable side-effects were found., Conclusion: In summary, this study indicates the significant efficiency of the 68 Ga labeled HER2 affibody. Preclinical and clinical studies support the possibility of monitoring HER2 levels in breast cancers using 68 Ga-NOTA-MAL-Cys-MZHER 2:342 ., Advances in Knowledge: The research investigated the feasibility of a 68 Ga labeled HER2 affibody modified with a hydrophilic linker for breast cancer PET imaging. Favorable outcomes showed that the probe might be valuable for determining HER2 status of the disease.

Background: Human epidermal growth factor receptor type 2 (HER2) is abundant in a wide variety of tumors and associated with the poor prognosis. Radiolabeled affibodies are potential candidates for detecting HER2-positive lesions. However, laborious multiple-step synthetic procedure and high abdomen background may hinder the widespread use. Herein, cysteinylated ZHER 2:342 modified with a new hydrophilic linker (denoted as MZHER 2:342 ) was designed and labeled using 18 FAl-NOTA strategies. The biologic efficacy of the novel tracer and its feasibilities for in vivo monitoring HER2 levels were also investigated in xenograft models with different HER2 expressions. Method: MZHER 2:342 was conjugated with MAL-NOTA under standard reaction conditions. The affibody molecule was then radiolabeled with 18 FAl complex. The binding specificity of the tracer, 18 FAl-NOTA-MAL-MZHER 2:342 , with HER2 was primarily characterized via in vitro studies. MicroPET imaging were performed in nude mice bearing tumors (SKOV-3, JIMT-1 and MCF-7) after injection. The HER2 levels of xenografts were determined using Western blotting analysis. Results: 18 FAl-NOTA-MAL-MZHER 2:342 can be efficiently produced within 30 min with a non-decaycorrected yield of about 10% and a radiochemical purity of more than 95%. In vitro experiments revealed that the modified affibody retained the specific affinity to HER2. PET imaging showed that SKOV-3 and JIMT-1 xenografts were clearly visualized with excellent contrast and low abdomen backgrounds. On the contrary, the signals of MCF-7 tumor were difficult to visualize. The ROI values ranged from16.54±2.69% ID/g for SKOV-3 to 8.42±1.20 %ID/g for JIMT-1 tumors at 1h postinjection respectively. Poor uptake was observed from MCF-7 tumors with 1.71±0.34% ID/g at the same time point. Besides, a significant linear correlation between % ID/g values and relative HER2 expression levels was also found. Conclusions: 18 FAl-NOTA-MAL-MZHER 2:342 is a promising tracer for in vivo detecting HER2 status with the advantages of facile synthesis and favorable pharmacokinetics. It may be useful in differential diagnosis, molecularly targeted therapy and prognosis of the cancers., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.