Synthesis and evaluation of [18F]fluorinated triazole-derivatives of the pittsburgh compound as potential PET radiotracers for imaging amyloid plaques

Alzheimer's disease (AD) is a neurodegenerative disease whose prevalence increases dramatically after the age of 65 years. The presence of β-amyloid plaques in the brain is a pathological feature of the disease. It is difficult to diagnose early stages of AD and to distinguish it from decline in cognitive function associated with memory loss due to the normal aging process. Neuron-imaging techniques, such as PET, play important role in diagnosis of the disease. Therefore, PET imaging probes with high affinity for β-amyloid plaques, capable of detecting low plaque load, are essential in application of PET imaging for presymptomatic identification of patients and monitoring drug treatment. We report progress on the synthesis and in vivo biodistribution of 18F-labeled triazole derivatives of the Pittsburgh compound as potential β-amyloid plaque imaging agents. 2-(4'-azidophenyl)-6-hydroxybenzothiazole was prepared from 2-(4'-nitrophenyl)-6-methoxybenzothiazole by first reducing the nitro to amino to 2-(4'-aminophenyl)-6-methoxybenzothiazole form then deprotecting and finally conversion of the amino to azide. The azide was then reacted with a variety of terminal alkynes under Click conditions using copper (II) sulfate / ascorbic acid as catalyst to form the target triazole-derivative of the Pittsburgh compound. The same azide will be reacted with [18F]fluorinated alkynes to form radiolabeled triazole derivatives of the Pittsburgh compound. In vitro binding affinity will be determined using [125I]IMPY competition experiment using aggregated Aβ(1-42)-peptide. The biodistribution in normal mice will be done by injecting a solution of 3.7MBq of the [18F]fluoro-triazole-derivative in saline containing 10% ethanol. 2-(4'-Azidophenyl)-6-methoxybenzothiazole was successfully synthesized from 2-(4'-aminophenyl)-6- methoxybenzothiazole in a reasonable yield of 43%. The azide was reacted with 3-phenyl-1-propyne and 4-pentyn-1-ol using copper (II) sulfate / ascorbic acid to give the corresponding triazole-containing derivatives after purification by flash chromatography or HPLC. Click chemistry was successfully used to synthesize triazole-containing derivatives of the Pittsburgh compound. Preparation of [18F]fluorinated triazole-containing derivatives, as PET imaging probes is in progress. The compounds will be used in imaging of transgenic mouse model of AD treated with quetiapine, a drug which is known to remove plaques, to determine the drug's effectiveness in treating AD mice.