A new highly deuterated [18F]AV-45, [18F]D15FSP, for imaging β-amyloid plaques in the brain

1600 Introduction: Amyvid (florbetapir f18, [18F]AV-45) is a FDA approved Positron Emission Tomography (PET) imaging agent targeting β-amyloid (Aβ) plaques in the brain. Literature reports suggest that [18F]AV-45 is metabolized rapidly in blood and some of its O-dealkylated metabolites led to production of [18F]F- and resulted in relatively high bone uptake. Deuterium substitution for hydrogen often increases in vivo metabolic stability through a reduction in drug metabolism. In an effort to slow down the in vivo metabolism, we report preclinical evaluation of deuterated derivate, [18F]D15FSP, and comparison with those of N-methyl deuterated [18F]D3FSP and non-deuterated [18F]AV-45. Methods: Radiolabeling procedures were achieved by a similar methods as [18F]AV-45. Preclinical pharmacology of [18F]D15FSP was evaluated using in vitro autoradiography, competitive binding assay and in vivo biodistribution in normal mice. Results for all three agents were compared. Results: [18F]D15FSP was prepared and purified (by HPLC) with ~47% yield (decay corrected) and > 95% purity (Scheme 1). Binding assays showed that D15FSP displayed excellent binding affinity (Ki = 7.52 nM) to Aβ aggregates, a similar value as D3FSP (Ki = 5.39 nM) and AV-45 (Ki = 5.18 nM). In vitro autoradiography of AD brain sections, [18F]D15FSP, [18F]D3FSP and [18F]AV-45 showed similar binding to Aβ plaques (Fig. 1). Biodistribution studies of all three agents in mice showed comparable initial brain uptake and very rapid washout in blood. Two deuterium substituted tracers, [18F]D15FSP and [18F]D3FSP, showed lower residual activity in the brain suggesting lower nonspecific binding. Particularly, a very low bone uptake at 120 min after iv injection was observed for [18F]D15FSP (1.44 %ID/g), comparing to [18F]D3FSP (4.23 %ID/g) and [18F]AV-45(4.03 %ID/g). Apparently, defluorination of [18F]D15FSP in mice was reduced as indicated by the lower bone uptake (Fig. 2). Conclusion: The highly deuterated Aβ imaging agent, [18F]D15FSP, displayed excellent Aβ binding, high initial brain penetration and low bone retention, suggesting that it might be suitable as a PET imaging agent for detecting amyloid plaques in AD patients.