Background <p>A new β-amyloid (Aβ) targeting radiotracer, [¹⁸F]D3FSP ([¹⁸F]P16-129), for diagnosis of Alzheimer’s disease (AD) is reported. This radiotracer is a deuterated N-methyl derivative of Amyvid (AV-45, florbetapir f18) which was FDA-approved in 2013. Deuteration may alter a tracer’s PK such that imaging performance is improved. A head-to-head comparison between these two imaging agents was conducted in AD patients. A separate biodistribution study was conducted on six healthy subjects, and radiation dosimetry estimation was obtained.</p> Results <p>Eight patients, clinically diagnosed with Alzheimer’s disease, had an average age of 61.1 ± 10.0 years, and an average MMSE score of 21 ± 4. Each patient underwent paired 90-minute dynamic PET/CT scans separately within a few weeks (323 ± 31 MBq of [¹⁸F]D3FSP or [¹⁸F]AV45; florbetapir f18). SUVR (50–70&#xa0;min) and Distribution Volume Ratio (DVR) of 43 brain regions were evaluated. The average SUVR across cortical gray matter was 1.65 ± 0.21 for [¹⁸F]AV45 and 1.65 ± 0.23 for [¹⁸F]D3FSP, while global DVRs were 1.36 ± 0.14 and 1.37 ± 0.13 for [¹⁸F]AV45 and [¹⁸F]D3FSP respectively. Strong correlations (R² = 0.8–0.9) were observed between tracers for both SUVR and DVR, with slopes of ~ 0.9 (SUVR) and ~ 1 (DVR). No image artifacts or confounds influenced the visual interpretation of [¹⁸F]D3FSP compared to [¹⁸F]AV45.</p> Conclusions <p>Results showed no difference between [¹⁸F]D3FSP and [¹⁸F]AV45 and no benefit of deuteration at the N-methyl site. Even so, [¹⁸F]D3FSP may be a useful alternative for PET/CT imaging of Aβ deposits in the brain as its binding characteristics were very similar to its non-deuterated analog, the FDA-approved drug [¹⁸F]AV45.</p> Trial registration <p>Clinicaltrials.org, NCT03902548. Registered 01/07/2018.</p>