Purpose <p>This study aims to compare [¹⁸F]Florbetazine (FBZ, [¹⁸F]92) with [¹¹C]Pittsburgh compound B (PiB) and [¹⁸F]Florbetapir (FBP) PET imaging to evaluate the diagnostic efficacy of FBZ and explore differences in topographical deposition patterns between FBZ and PiB/FBP.</p> Methods <p>Seventy-eight participants were included, with 40 in the FBZ-PiB subgroup (9 healthy controls [HCs], 9 with non-AD dementia, and 22 with AD) and 38 in the FBZ-FBP subgroup (10 HCs, 9 with non-AD dementia, 1 with mild cognitive impairment [MCI], and 18 with AD). All images were visually evaluated by two trained nuclear medicine physicians and quantitatively analyzed using global and regional standardized uptake value ratio (SUVr).</p> Results <p>Visual interpretation of FBZ scans achieved a diagnostic sensitivity of 100% and a specificity of 97%, with complete concordance with PiB and FBP. Positive FBZ PET scans showed higher gray matter uptake relative to white matter, closely resembling the cortical distribution of PiB but offering greater gray-to-white matter contrast compared to both PiB (1.19(0.17) vs. 1.11(0.15), <i>P</i> &lt; 0.001) and FBP (1.27(0.24) vs. 0.86(0.13), <i>P</i> &lt; 0.001). The global SUVr for all three radiotracers demonstrated perfect diagnostic accuracy for AD, with a cut-off range of 0.99 to 1.38 for FBZ when using the whole cerebellum as a reference. The global SUVr of FBZ strongly correlated with PiB (slope = 0.94, <i>r</i> = 0.99, <i>P</i> &lt; 0.001) and FBP (slope = 1.74, <i>r</i> = 0.95, <i>P</i> &lt; 0.001).</p> Conclusion <p>FBZ PET imaging exhibits comparable diagnostic efficacy to PiB and FBP, with excellent correlation for Aβ quantification. Its high cortical uptake and low white matter binding favors visual interpretation in clinical practice.</p> Clinical trial registration <p>NCT06141356. Registered November 2023. <a href="https://clinicaltrials.gov/search?term=NCT06141356">https://clinicaltrials.gov/search?term=NCT06141356</a>.</p>