Background: Distinguishing unilateral aldosterone-producing adenomas (APA) from idiopathic hyperaldosteronism (IHA), nonfunctional adrenal adenoma (NFA), and pheochromocytoma (PHEO) within primary aldosteronism (PA) presents a significant challenge.Studies have demonstrated high levels of chemokine receptor (CXCR) 4 expression in APA, thereby validating the use of 68 Ga-labeled CXCR4 PET/CT for detecting APA.This study evaluates the efficacy of [ 18 F]AlF-NOTA-pentixather PET/CT in distinguishing APA from other PA types.Methods: In the initial experiment, a comparative analysis was conducted to evaluate the diagnostic efficacy of [ 18 F]AlF-NOTA-T140 PET/CT and [ 18 F]AlF-NOTA-pentixather PET/CT for APA in 3 patients with PA.Based on the preliminary findings, [ 18 F]AlF-NOTA-pentixather PET/CT was subsequently performed on 45 patients with suspected PA and 5 controls.Lesions exhibiting higher tracer uptake than normal adrenal glands were considered positive and referred for adrenalectomy.Prior to surgery, adrenal venous sampling (AVS) was performed in 71.1% of patients to assess laterality.Postoperative follow-up was conducted in 91.1% of patients.The semi-quantitative analysis involved assessing maximum standardized uptake value (SUVmax), LLR (lesion-to-liver ratio), and lesion-to-contralateral ratio (LCR).Correlations were made between PET/CT findings, histopathology results, outcomes, and AVS.Results: In terms of diagnosing APA, [ 18 F]AlF-NOTA-pentixather PET/CT demonstrated a sensitivity of 100%, specificity of 91.7%, and accuracy of 95.8%.The mean SUVmax for APAs (25.62 12.71, n = 24) was significantly higher compared to non-APA cases (7.24 3.27, n = 24, P < 0.0001).An optimal SUVmax threshold of 11.60 accurately predicted the presence of APA with a sensitivity of 95.8%, specificity of 96.0%, and accuracy of 93.9%.A cutoff value for LCR at 1.38 provided 95.8% sensitivity and 92.0%specificity, while an LLR cutoff at 5.28 yielded a sensitivity rate of 91.7% and a specificity rate of 92.0%.Positive findings on PET/CT scans were completely consistent with AVS results.All patients with positive lesions derived significant benefits from surgical intervention. Ivyspring