First-in-human evaluation of [ ¹⁸ F]-AlF-NOTA-neurotensin for NTSR1-targeted imaging of prostate cancer: a head-to-head comparison with [ ⁶⁸ Ga]Ga-PSMA-617

Background Neurotensin receptor-1 (NTSR1) is a promising target for prostate cancer imaging. This study evaluates the first-in-human NTSR1-directed radiotracer [18F]-AlF-NOTA-neurotensin and compares it with [68Ga]Ga-PSMA-617.Methods In a single-centre, prospective study, 23 men with biopsy-verified prostate cancer were enrolled at Xiangya Hospital (June 2020–June 2024). Within 7 days before radical prostatectomy, whole-body PET/CT was performed after sequential administration of [68Ga]Ga-PSMA-617 and [18F]-AlF-NOTA-neurotensin. Imaging metrics were assessed against histopathology. Immunohistochemistry (IHC) for PSMA and NTSR1 was conducted to correlate tracer uptake with receptor expression.Results The median age was 71 years (IQR 66–75); 14 were treatment-naïve and 9 had prior androgen-deprivation therapy (ADT). In untreated patients, [68Ga]Ga-PSMA-617 showed superior sensitivity (92.9%), specificity (100%), PPV (100%), and NPV (93.3%) compared to [18F]-AlF-NOTA-neurotensin . At the lesion level, [68Ga]Ga-PSMA-617 localized 36 of 38 foci (94.7%), while [18F]-AlF-NOTA-neurotensin identified none (0%; p < 0.05). After short-term ADT, [68Ga]Ga-PSMA-617 sensitivity dropped to 33.3%, while [18F]-AlF-NOTA-neurotensin sensitivity rose to 77.8% (p < 0.05). Lesion-based detection rates were 36% and 64%, respectively, and there were no significant differences in specificity, PPV, or NPV. IHC revealed a significant decrease in PSMA H-score from 9 (IQR 6.5–12) to 7 (IQR 1.3–8.8; p = 0.034) and an increase in NTSR1 H-score from 1 (IQR 0.25–2) to 6 (IQR 3–8; p = 0.003).Conclusion [68Ga]Ga-PSMA-617 remains the gold standard for treatment-naïve prostate cancer, whereas [18F]-AlF-NOTA-neurotensin provides complementary-diagnostic value by enhancing lesion detection after ADT. Our findings support a stage-adapted, receptor-driven imaging strategy that addresses tumor phenotypic heterogeneity, enabling more precise management throughout the disease course.