Historical efforts to develop ^99mTc-based amyloid plaque targeting radiotracers

Imaging biomarkers have changed the way we study Alzheimer's disease and related dementias, develop new therapeutics to treat the disease, and stratify patient populations in clinical trials. With respect to protein aggregates comprised of amyloid-β plaques and tau neurofibrillary tangles, Positron Emission Tomography (PET) has become the gold standard imaging modality for quantitative visualization. Due to high infrastructural costs, the availability of PET remains limited to large urban areas within high income nations. This limits access to leading edge medical imaging, and potentially access to new treatments, by millions of rural and remote residents in those regions as well as billions of people in middle- and low-income countries. Single Photon Emission Computed Tomography (SPECT) is a more widely available imaging alternative with lower infrastructural costs and decades of familiarity amongst nuclear medicine professionals. Recent technological advances have closed the gap in spatial resolution and quantitation between SPECT and PET. If effective SPECT radiotracers were available to visualize amyloid-β plaques, geographic barriers to imaging could be circumvented. In this review, we will discuss past efforts to develop SPECT radiotracers targeting amyloid-β plaques which incorporate the most used radionuclide in nuclear medicine: technetium-99m (^99mTc; t _1/2 = 6.01 h; γ = 140 keV). While reviewing the various chemical scaffolds and chelates employed, the focus will be upon the impact to the pharmacological properties of putative ^99mTc-based amyloid-targeting radiotracers.