Synthesis and structure-activity relationship of Tc/Re 2-arylbenzothiazoles as β-amyloid imaging agents

1555 Objectives PET tracers for imaging brain β-amyloid (Aβ) plaque have been successfully applied in clinical studies of Alzheimer’s disease (AD). These include 2-arylbenzothiazoles (2-ABTs) [11C]PiB and [18F]Flutemetamol developed at the University of Pittsburgh. In this study, we aim at exploring 99mTc labeled 2-ABTs for imaging Aβ plaques with the less expensive and more accessible imaging modality SPECT. Methods Re 2-ABTs were synthesized via the integrated approach to minimize the overall molecular weight. The binding affinity was measured using synthetic Aβ1-40 fibrils, and the lipophilicity was determined using their HPLC partition coefficients PC18 as an estimation. 99mTc labeling was performed by direct labeling using SnCl2 as the reducing agent. The ability to cross blood-brain barrier was determined by brain uptake in mice at 2 min postinjection (pi). Results By using Re as a surrogate of Tc, a total of 35 neutral and compact Re 2-ABTs with an integrated N3S, N2S2, or N2SO chelator were prepared. These Re 2-ABTs are lipophilic (logPC18= 0.67-3.25) and bind to Aβ1-40 fibrils with a range of affinities (Ki= 29.7-861 nM). Re 2-ABTs with a diaminedithiol or diamine-thiol-phenol chelator integrated at the 3’ and 4’ positions of the phenyl group show better binding affinity to Aβ1-40 fibrils (Ki= 29.7-109 nM). The 99mTc analog of the most potent Re 2-ABT (Ki= 29.7nM; logPC18= 1.65) was prepared in >80 % radiochemical yield and its uptake in mouse brain at 2 min pi was 0.27 %ID/g. Conclusions The 99mTc-labeled 2-ABT reported here is not suitable for imaging Aβ plaques in the brain parenchyma of AD patients due to its limited ability to cross the blood-brain barrier. However, without high background interference from brain parenchyma it might be advantageous to use 99mTc-labeled 2-ABT for imaging Aβ deposition in blood vessels known as cerebral amyloid angiopathy, a common cause of hemorrhagic stroke and dementia in the elderly