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

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 Aβ_1-40 fibrils, and the lipophilicity was determined using their HPLC partition coefficients P_C18 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 (logP_C18= 0.67-3.25) and bind to Aβ_1-40 fibrils with a range of affinities (K_i= 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 Aβ_1-40 fibrils (K_i= 29.7-109 nM). The ^99mTc analog of the most potent Re 2-ABT (K_i= 29.7nM; logP_C18= 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