Tc-Labeled pyridyl benzofuran derivatives to target β-amyloid plaques

In developed countries, Alzheimer’s disease (AD) affects ~1% of the individuals who are ≥65 years old and roughly 30% of those who are ≥80 years of age (2). The disease is characterized by slow deposition of the amyloid beta protein (βA) and formation of neurofibrillary tangles in the memory and cognition regions of the brain, which lead to memory loss and cognitive impairment in the individual (3). The generation of βA from its precursor, the amyloid precursor protein, has been illustrated by Tam and Pasternak (2), and the biochemistry of this protein and the amyloid deposits in AD has been discussed by Masters and Selkoe (4). Because the deposition of βA in the brain starts several years before the symptoms of AD are apparent, detection of the disease at an early stage can assist in the diagnosis, improved monitoring of the disease, and the development of a therapeutic regimen that can slow the advancement of AD (1). Although several drugs approved by the United States Food and Drug Administration (FDA) are available to treat the symptoms of AD, none of these medications prevent the onset and progression of the disease. Imaging probes for use with positron emission tomography (PET) have been evaluated under preclinical conditions for the noninvasive visualization of AD (1), and F-labeled AV45 (florbetapir) was approved by the FDA to estimate the density of βA neuritic plaque in the brains of AD patients. Cheng et al. showed that F-labeled 5-(5-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)benzofuran-2-yl)-N,N-dimethylpyridin-2-amine ([F]FPYBF), a derivative of benzofuran, had a high affinity for βA plaques, can label the plaques in postmortem human AD brain sections, and is suitable for the visualization of βA deposits in brain sections of mice (a murine model of AD) injected with [F]FPYBF (5). Similar observations have been reported from biodistribution studies with two other F-labeled derivatives of benzofuran (6). A common limitation of these PET imaging compounds (under development or approved by the FDA) is that the tracers have a short half-life (e.g., the half-life of the most commonly used radionuclides for PET imaging, such as C, F, and Ga, are 20.4 min, 109.8 min, and 67.6 min, respectively), may not establish the presence of βA plaques in the brain with certainty, and cannot be used to monitor the therapeutic response in an AD patient. As an alternative to detect βA plaques with PET, investigators have evaluated the use of several Tc-labeled compounds (half-life of Tc is 6 h) with single-photon emission computed tomography (SPECT) (1). However, most of these radiolabeled chemicals have been used to visualize the plaques in sections of mouse and human brains with AD and do not exhibit a high affinity for the βA plaques or can not cross the blood–brain barrier (BBB) in the animals (1). On the basis of results obtained with the benzofuran derivatives mentioned above (5, 6), Tc-labeled pyridyl benzofuran (Bp) derivatives were synthesized, and the biodistribution of these tracers was investigated in normal mice (1). To label the Bp derivatives with Tc, a compact chelating agent, bis(aminoethanethiol) (BAT), was conjugated to the compounds to generate radiolabeled probes (designated [Tc]BAT-Bp-1, [Tc]BAT-Bp-2, and [Tc]BAT-Bp-3).