Development of 18F-FBM for Detecting of Β-Amyloid Plaques and Neurofibrillary Tangles In

Further Development of 18F-FBM for detecting of β-Amyloid Plaques and Neurofibrillary Tangles in Alzheimer’s disease

Amish Doshi

Mentor: Jogeshwar Mukherjee

Alzheimer’s disease (AD) is characterized by the presence of neurofibrillary tangles (NFT) and beta-amyloid (Aβ) plaques in the brain. The disease causes memory damage and continuous cognitive decline. To detect the plaques and tangles at an earlier stage, positron emission tomography (PET) is used as an imaging method for early diagnosis. A compound by the name of 18F-FBM (4’-[(2-[18F] fluoroethyl) (methyl) amino]-4-phenyl-3-buten-2-malonitrile) has been synthesized in our laboratories and has been shown to bind to plaques and tangles. 18F-FBM has a less lipophilic structure than previous AD imaging agents, enabling more accurate detection of plaques and tangles. Synthesis starts with N-methyl-N-(2-hydroxyethyl)-4-aminobenzaldehyde and follows a three-step synthesis to obtain the tosylate precursor of FBM, which is radiolabeled to give 18F-FBM. The goal of this project was to develop improved methods of synthesis of FBM and the precursor tosylate for making 18F-FBM. Synthesis methods of the intermediate ketone, 4’-[(2-Hydroxyethyl) (methyl) amino]-4-phenyl-3-buten-2-one were improved to provide higher yields of the product, with fewer impurities. Methods to improve the yield and purity of the malonitrile, 4’-[(2-hydroxyethyl) (methyl) amino]-4-phenyl-3-buten-2-malonitrile are currently underway. Radiosynthesis is ongoing for studies using transgenic AD mice. We will use two mice models for AD; Tg2576 (develops plaques) and 3xTg (develops both plaques and tangles). Our previous preliminary results have shown successful binding of 18F-FBM to brain regions—including the hippocampus and frontal cortex—known to contain plaques and tangles. Lower binding was seen in the cerebellum, which is known to contain few plaques and tangles. We plan to conduct in vivo studies using 18F-FBM and the AD mice models and imaging using the Preclinical Inveon scanner in the MicroPET Imaging Facility.