[68Ga]-2(Griffith University)

[⁶⁸Ga]Ga-RM2 is a novel gastrin-releasing peptide receptor antagonist with emerging diagnostic utility in low-grade breast cancer (BC) expressing estrogen receptors (ER). This systematic review and meta-analysis evaluates the current diagnostic utility of [⁶⁸Ga]Ga-RM2 PET/CT and explores BC tumor uptake metrics in ER-positive BC lesions. A systematic search of PubMed, Scopus, and Web of Science databases was conducted using relevant keywords to extract, screen, and select eligible data for analysis. Out of 182 articles reviewed, only four studies were found eligible for inclusion. Qualitative data analysis was applied to four included papers meeting the eligibility criteria. Various promising utilities were identified, including [⁶⁸Ga]Ga-RM2's ability to detect ER-positive primary BC lesions, lymph nodes, and distant metastatic lesions. Additionally, recent studies have addressed its potential for assessing therapy response following neoadjuvant chemotherapy. Importantly, [⁶⁸Ga]Ga-RM2 has demonstrated clinical utility in improving and guiding proper management planning by detecting metastatic lesions that can alter overall staging and treatment strategies. The overall lesion detectability was 93% (95% CI: 87-98%) for ER-positive BC. ER-positive BC lesions showed significantly higher maximum standardized uptake values (SUVmax) compared to ER-negative lesions, with a weighted mean difference (WMD) of 10.6 (95% CI: 8.1-13.2; P < 0.00001). Furthermore, ER-positive BC lesions exhibited statistically significant higher SUVmax compared to normal background breast tissue SUVmean, with an overall WMD of 9.9 (95% CI: 7.5-12.2; P < 0.00001). Further studies utilizing this promising radiotracer should be encouraged, implementing prospective, large-scale designs in the near future.

Angiotensin-converting enzyme 2 (ACE2) is not only a key to the renin-angiotensin-aldosterone system and related diseases, but also the main entry point on cell surfaces for certain coronaviruses, including severe acute respiratory syndrome coronavirus (SARS-CoV) and SARS-CoV-2. By analyzing the different key binding sites from the receptor-binding domain (RBD) of SARS-CoV and SARS-CoV-2, nine new ACE2-targeting peptides (A1 to A9) were designed, synthesized and connected with a chelator, 1,4,7-triazacyclononane-N,N',N''-triacetic acid (NOTA). NOTA-A1, NOTA-A2, NOTA-A4, NOTA-A5, and NOTA-A8 were successfully labeled with [⁶⁸Ga]Ga³⁺ and were used for biological evaluation. [⁶⁸Ga]Ga-NOTA-A2, [⁶⁸Ga]Ga-NOTA-A5, and [⁶⁸Ga]Ga-NOTA-A8 showed specific binding to ACE2 via cell assays, and their binding sites and binding capacity were calculated by molecular docking and molecular dynamics simulations. In tumor-bearing mice, A549 tumors were visualized 60 min postinjection of [⁶⁸Ga]Ga-NOTA-A2, [⁶⁸Ga]Ga-NOTA-A5, or [⁶⁸Ga]Ga-NOTA-A8. These peptides also accumulated in the organs with high-level ACE2 expression, confirmed by immunohistochemical stain. Among them, [⁶⁸Ga]Ga-NOTA-A5 exhibited the highest tumor uptake and tumor/background ratio, and it successfully tracked the increased ACE2 levels in mice tissues after excessive Losartan treatment. In a first-in-human study, the distribution of [⁶⁸Ga]Ga-NOTA-A5 was evaluated with positron emission tomography/computed tomography (PET/CT) in three participants without adverse events. ⁶⁸Ga-labeled peptides originated from the coronavirus RBD, with [⁶⁸Ga]Ga-NOTA-A5 as a typical representative, seem to be safe and effective for the evaluation of ACE2 expression in vivo with PET/CT, facilitating further mechanism investigation and clinical evaluation of ACE2-related diseases.