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Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104, USA; Five Eleven Pharma Inc., Philadelphia, PA 19104, USA. Electronic address:
Published: April 2019
AI Article Synopsis
Article Abstract
Introduction: Alzheimer's disease is a common neurodegenerative disease that is characterized by the presence of Aβ plaques in the brain. The FDA has approved the use of Amyvid (florbetapir f18, AV-45) as a PET imaging agent for detecting Aβ plaques in the living human brain. In an attempt to reduce N-demethylation in vivo by taking advantage of more stable C-D bonds, an analog of AV-45, [F]D3FSP ([F]7), was synthesized to improve image contrast for detecting and monitoring the Aβ plaques. A convenient and improved preparation of [F]D3FSP ([F]7) is needed for widespread clinical application. We report herein the optimization of the radiosynthesis and solid-phase extraction (SPE) procedure.
Methods: Radiosyntheses of [F]D3FSP ([F]7) under different fluorination conditions were evaluated, and the intermediate, containing an N-Boc protecting group, was deprotected using different acids. One of the major objectives was to simplify the final purification step via SPE to avoid the commonly employed HPLC purification and maximize the radiochemical yields of [F]D3FSP ([F]7) while simultaneously removing several chemical impurities (pseudocarriers). Washing various solid-phase cartridges with different combinations of ethanol/water and acetonitrile/water was explored to optimize the purification step. To evaluate the potential interference in Aβ plaques imaging from the presence of pseudocarriers, each chemical was identified and quantified by LC/MS and HPLC. An in vitro binding assay was employed to evaluate the binding affinities of [F]D3FSP ([F]7) and the pseudocarriers to Aβ plaques using postmortem AD brain tissue.
Results: Using the optimized radiosynthesis method and SPE purification, the final dose of [F]D3FSP ([F]7) was obtained in 50 min with a very low content of pseudocarriers (21.7 ± 5.5 μg). The radiochemical yield was 44.4 ± 5.7% (decay corrected), and the radiochemical purity was >95%. SPE-purified doses of [F]D3FSP ([F]7) displayed excellent binding affinity and specificity for Aβ plaques as measured in an in vitro binding assay using AD brain homogenates, and the OH-pseudocarrier, 8 (K = 19.5 ± 0.5 nM), and the Cl-pseudocarrier, 10 (K = 18.6 ± 3.9 nM), showed lower binding affinities for Aβ plaques than those of AV-45 (K = 8.6 ± 0.5 nM) and D3FSP, 7 (K = 9.8 ± 0.5 nM).
Conclusions: An optimized radiosynthesis and fast SPE purification method suitable for the preparation of clinical doses of [F]D3FSP ([F]7) was accomplished. The results of quality control tests and binding studies suggested that the SPE-purified doses of [F]D3FSP ([F]7) are appropriate for imaging Aβ plaques in the human brain.
