Abstract
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Objectives The accumulation of neurofibrillary tangles composed of aggregates of hyperphosphorylated tau proteins in brain is one of the neuropathological hallmarks of Alzheimer’s disease (AD). Because in vivo imaging of the tau aggregates may provide useful information on the progression of AD, several PET tracers targeting tau aggregates, including [18F]AV1451, [18F]THK-5351, and [11C]PBB3, have been developed and tested clinically. Resent results of clinical research have demonstrated the usefulness of tau imaging for AD diagnosis. On the other hand, useful SPECT tracers for imaging tau aggregates have never been reported. In SNMMI 2015, we reported radioiodinated benzoimidazopyridine (BIP) derivatives (BIP-1 and BIP-2) as novel tau imaging tracers for SPECT. While these derivatives showed selective binding for tau aggregates, further enhancement of affinity for tau aggregates was necessary for the development of clinically useful tau-SPECT tracers. In this study, we designed and synthesized three novel BIP derivatives with methyl (BIP-3), methoxy (BIP-4), and dimethylamino (BIP-5) groups, and evaluated their utility as SPECT tracers for in vivo imaging of tau aggregates in AD brains.
Methods [125I]BIP derivatives were successfully prepared through an iododestannylation reaction from the tributyltin derivatives. In vitro autoradiographic studies were performed using postmortem AD brain sections to evaluate specific binding of these derivatives to tau. Brain uptake and clearance were measured in normal mice after injection of [125I]BIP derivatives. In addition, we tested in vivo stability of the BIP derivatives in normal mice.
Results /b> All [125I]BIP derivatives were successfully prepared in high radiochemical yields (30 - 65%) and purities (>99%). In in vitro autoradiographic studies using postmortem AD brains, these derivatives displayed high and selective accumulation of radioactivity in the positive region of tau aggregates, while no marked accumulation was observed in the brain sections deposited with onlyβ-amyloid aggregates. Among them, [125I]BIP-5 which has the dimethylamino group showed highest accumulation of radioactivity in the tau positive region. In addition, this accumulation was inhibited in the presence of BIP-5. These results suggested that [125I]BIP-5 bound to tau aggregates selectively. In biodistribution study using normal mice, [125I]BIP derivatives showed high brain uptake at 2 min postinjection (3.5 - 4.3% ID/g) and rapid clearance at 60 min post injection (0.1 - 0.2% ID/g). When tested in vivo stability in normal mice, these derivatives exhibited high stability in blood and brain.
Conclusions The results in the present study suggested that [123I]BIP-5 may be a useful SPECT tracers for in vivo imaging of tau aggregates in AD.