Purpose <p>This study aimed to compare the diagnostic efficacy and clinical management impact of [¹⁸F]AlF-NOTA-LM3 with [⁶⁸Ga]Ga-DOTATATE or [⁶⁸Ga]Ga-NODAGA-LM3 in patients with well-differentiated neuroendocrine tumors.</p> Methods <p>Patients with histologically confirmed well-differentiated NETs were prospectively recruited and randomized into two arms: Arm A, undergo [¹⁸F]AlF-NOTA-LM3 and [⁶⁸Ga]Ga-DOTATATE PET/CT; Arm B, undergo [¹⁸F]AlF-NOTA-LM3 and [⁶⁸Ga]Ga-NODAGA-LM3 PET/CT. Biodistribution, lesion numbers, and lesion uptake were compared. The impact on clinical management was evaluated. Additionally, a post-hoc analysis of the sensitivity of [¹⁸F]AlF-NOTA-LM3 and ⁶⁸Ga-labeled tracers was evaluated.</p> Results <p>A total of 78 patients were included in this study: 38 in Arm A and 40 in Arm B. [¹⁸F]AlF-NOTA-LM3 showed lower abdominal organ uptake than [⁶⁸Ga]Ga-DOTATATE and [⁶⁸Ga]Ga-NODAGA-LM3. [¹⁸F]AlF-NOTA-LM3 was superior to [⁶⁸Ga]Ga-DOTATATE in liver (684 vs. 449, <i>P</i>&lt;0.001) and lymph node lesion (41 vs. 29, <i>P</i> = 0.005) detection, and superior to [⁶⁸Ga]Ga-NODAGA-LM3 in liver lesion (625 vs. 490, <i>P</i> = 0.001) detection. The lesion-level sensitivity of [¹⁸F]AlF-NOTA-LM3 was significantly higher than that of [⁶⁸Ga]Ga-DOTATATE (90.6% vs. 67.6%, <i>P</i>&lt;0.001) and [⁶⁸Ga]Ga-NODAGA-LM3 (90.9% vs. 81.0%, <i>P</i>&lt;0.001), particularly for liver metastases. [¹⁸F]AlF-NOTA-LM3 led to a clinical management change in 18.5% (7/38) of patients in Arm A and 12.5% (5/40) of patients in Arm B: 13.2% (5/38) in Arm A and 7.5% (3/40) in Arm B with major changes, while 5.3% (2/38) in Arm A and 5% (2/40) in Arm B with minor changes.</p> Conclusion <p>[¹⁸F]AlF-NOTA-LM3 shows superior diagnostic efficacy than [⁶⁸Ga]Ga-DOTATATE and [⁶⁸Ga]Ga-NODAGA-LM3. [¹⁸F]AlF-NOTA-LM3 demonstrates significant value in guiding clinical decision-making in a subgroup of patients.</p> Trial registration <p>ClinicalTrials.gov identifier NCT06056362.</p>