First-in-human study of an optimized, potential kit-type, SSTR antagonist <sup>68</sup>Ga-DATA<sup>5m</sup>-LM4 in patients with metastatic neuroendocrine tumors
Authors: Jingjing Zhang, Lukas Greifenstein, Vivianne Jakobsson, Elcin Zan, Andre Klega, Frank Rösch, Christian Landvogt, Corinna Mueller, Richard P Baum
Journal: Theranostics (2025)

Radiolabeled somatostatin receptor (SSTR) agonists 68Ga-DOTA-TATE and 68Ga-DOTA-TOC are widely applied for imaging of patients with neuroendocrine tumors (NETs). Preclinical and preliminary clinical evidence has indicated that SSTR antagonists perform better for NET imaging. In this study, we assessed the feasibility of using a new hybrid chelator DATA5m ((6-pentanoic acid)-6-(amino)methyl-1,4-diazepinetriacetate))-conjugated kit-type SSTR antagonist 68Ga-DATA5m-LM4 for PET and evaluated the safety, biodistribution, and preliminary diagnostic efficacy of 68Ga-DATA5m-LM4 in patients with metastatic NETs. Methods: The DATA5m-conjugated form of LM4, was labeled with 68Ga. A total of 27 patients (19 men/8 women; mean age 61 years) with histopathologically confirmed well-differentiated NETs underwent 68Ga-DATA5m-LM4 PET/CT for the staging and restaging or patient selection for PRRT. All the patients underwent PET/CT scans 60 min after intravenous bolus injection of 1.85 MBq (0.05 mCi) per kilogram of body weight (151 ± 54 MBq mean ± SD) of 68Ga-DATA5m-LM4. Results: DATA5m-LM4 was successfully labeled with 68Ga, achieving high yield and purity. After decay correction, radiochemical yields (RCYs) of 80-95% and radiochemical purities (RCP) greater than 98% were obtained. 68Ga -DATA5m-LM4 was well tolerated in all patients, without clinically relevant adverse effects. A significantly lower uptake in normal liver parenchyma was observed with 68Ga-DATA5m-LM4 compared to 68Ga-DOTA-TATE PET/CT (3.90 ± 0.88 vs. 9.12 ± 3.64, P < 0.000001). Additionally, uptake in the thyroid gland, pancreas, and spleen was also lower (P < 0.05). 14 patients underwent 68Ga-DOTA-TOC PET/CT. 68Ga-DATA5m-LM4 uptakes in the liver and spleen were significantly lower than those of 68Ga-DOTA-TOC uptake (3.70 ± 0.79 vs. 5.33 ± 2.43, P = 0.0397; 11.88 ± 6.88 vs. 26.55 ± 16.07, P = 0.0022). Tumor lesions showed high uptake intensity on 68Ga-DATA5m-LM4 PET/CT, with the highest SUVmax up to 167.93 (mean ± SD, 44.47 ± 36.22). With SUVmean of healthy liver, kidneys, and blood pool as background to normalize the SUVmax of the single most intense lesion, tumor-to-background ratios were 20.32 ± 19.97 (range, 3.40 - 98.78) and 4.30 ± 3.03 (range, 0.65 - 14.70), 38.63 ± 35.97 (range, 4.1 - 173.12), respectively. Conclusion: This study demonstrated that the novel SSTR antagonist 68Ga-DATA5m-LM4 can be efficiently labeled with high radiochemical yield and purity, supported by a highly convenient production process. The tracer exhibited excellent imaging performance, with a highly favorable biodistribution characterized by high tumor contrast and minimal uptake in normal organs, particularly the liver, enabling superior lesion detection. The practical advantages of this straightforward labeling process, achieved without any apparent loss in diagnostic efficacy, offer a significant benefit over other competing antagonists. The ease of production, including the potential for a "kit-type" labeling method, makes 68Ga-DATA5m-LM4 an overall extraordinarily promising radiopharmaceutical for the staging and restaging of NET patients.