Synthesis and β-amyloid binding properties of rhenium 2-arylbenzothiazoles

Objectives Radiolabeled 2-arylbenzothiazoles (2-ABTs) including [¹¹C]PIB and [¹⁸F]AH110690 are useful PET tracers for imaging the deposition of β-amyloid (Aβ) plaque, a hallmark of Alzheimer’s disease. In this study we synthesized and evaluated Re 2-ABTs as our first step toward the development of ^99mTc PIB analogs for widespread use with SPECT.

Methods Re 2-ABTs were synthesized via the integrated approach to minimize the overall molecular weight (<550 daltons) . The binding affinity was measured using synthetic Aβ(1-40) fibrils, and the lipophilicity was determined by measuring the reverse phase HPLC partition coefficients P_C18 as an estimation.

Results Eight neutral and compact Re 2-ABTs (compounds 1-8) with a built-in triamine-thiol, diamine-dithiol, or diamine-thiol-phenol tetradentate chelator were prepared. The Re complexation was achieved via an exchange labeling reaction using a labile Re complex Re(V)O(PPh₃)₂Cl₃. Compounds 1-8 were isolated in 7-41% yields. In spite of potential existence of cis- and anti-isomers, only one single isomer was isolated in the preparation of 1-8. These Re compounds are lipophilic (logP_C18 = 1.14 – 2.59), and bind to synthetic Aβ(1-40) fibrils with good affinities (Ki = 29.7 – 140 nM).

Conclusions Our preliminary results have demonstrated that it is feasible to obtain compact, neutral, and lipophilic Re 2-ABTs with good binding affinity to aggregated Aβ. Further modification to obtain Re 2-ABTs with ever higher binding affinity is needed since most of the Aβ imaging agents currently used in clinical studies have binding affinities <10 nM.