2-(4-(2-[F]Fluoroethyl)piperidin-1-yl)benzo[4,5]imidazo[1,2-a]pyrimidine

Alzheimer's disease (AD) is a form of dementia with a gradual memory loss and a progressive decline in mental functions over time (1, 2). It is characterized pathologically by neuronal loss, extracellular senile plaques (aggregates of amyloid-β (Aβ) peptides consisting of 40–42 amino acids formed as the proteolytic cleavage of Aβ protein precursor (AβPP)), and intracellular neurofibrillary tangles (filaments of microtubule-binding hyper-phosphorylated protein tau) in the brain, especially in the hippocampus and associative regions of the cortex (3, 4). Aβ plaques and tau neurofibrillary tangles are implicated as the main causes of neuronal degeneration and cell death in AD patients (5, 6). Early diagnosis of AD is important for treatment consideration and disease management (7). Various Aβ imaging agents have been developed for magnetic resonance imaging, single-photon emission computed tomography, and positron emission tomography (PET) (8-14). The binding properties of different derivatives of Congo red, thioflavin, stibene, and aminonaphthalene have been studied in postmortem human brain tissue and in transgenic mice (Nesterov, E.E., 2005; Ran, C., 2009). Of these analogs, 2-(1-(6-[(2-[F]fluoroethyl)(methyl)amino]-2-naphthyl)ethylidene)malono nitrile ([F]FDDNP) has been studied in humans, showing more binding in the brains of patients with AD than in those of healthy people (15). [F]FDDNP has been found to bind to both Aβ plaques and tau neurofibrillary tangles. However, [F]FDDNP exhibits low signal/noise ratios for PET imaging because it is highly lipophilic. -methyl-[C]-2-(4'-methylaminophenyl)-6-hydroxybenzothiasole, an Aβ-binding compound based on a series of neutral thioflavin-T derivatives, was radiolabeled with the positron-emitting radionuclide C ([C]6-OH-BTA-1 or [C]PIB). [C]6-OH-BTA-1 was found to be a promising imaging agent for Aβ plaques in the brain (10). Okamura et al. (16) identified a series of quinolone derivatives that bind tau neurofibrillary tangles with higher affinity than Aβ plaques. One of these derivatives, 2-(4-aminophenyl)-6-(2-([F]fluoroethoxy))quinolone ([F]THK523), was shown with PET imaging to have higher brain accumulation in tau transgenic mice than in Aβ transgenic mice (17). Zhang et al. (18) evaluated 2-(4-(2-[F]fluoroethyl)piperidin-1-yl)benzo[4,5]imidazo[1,2-a]pyrimidine ([F]T808) as a PET imaging agent for tau pathologies.