Evaluation of ⁶⁴Cu-Based Radiopharmaceuticals that Target Aβ Peptide Aggregates as Diagnostic Tools for Alzheimer’s Disease

Abstract

Positron emission tomography (PET) imaging agents that detect amyloid plaques containing amyloid beta (Aβ) peptide aggregates in the brain of Alzheimer’s disease (AD) patients have been successfully developed and recently approved by the FDA for clinical use. However, the short half-lives of the currently used radionuclides 11C (20.4 min) and 18F (109.8 min) may limit the widespread use of these imaging agents. Therefore, we have begun to evaluate novel AD diagnostic agents that can be radiolabeled with 64Cu, a radionuclide with a half-life of 12.7 h, ideal for PET imaging. Described herein are a series of bifunctional chelators (BFCs), L1–L5, that were designed to tightly bind 64Cu and shown to interact with Aβ aggregates both in vitro and in transgenic AD mouse brain sections. Importantly, biodistribution studies show that these compounds exhibit promising brain uptake and rapid clearance in wild-type mice, and initial microPET imaging studies of transgenic AD mice suggest that these compounds could serve as lead compounds for the development of improved diagnostic agents for AD.

A Bispidol Chelator with a Phosphonate Pendant Arm: Synthesis, Cu(II) Complexation, and 64Cu Labeling

“…(i) fast radiolabelling (a few minutes to one hour) at room temperature and around physiological pH; (ii) high in vivo stability and kinetic inertness towards transmetallation, transchelation and reduction; and (iii) easy access synthesis and bioconjugation. 33,34 Chart 1. Structure of acid functionalized ligands (L 1 -L 2 ) studied and the related bispidone (L 3 ).…”

Metal-based imaging agents: progress towards interrogating neurodegenerative disease

“…More recently, Mirica and co-workers reported a series of 64 Cu-PET agents (TACNL 1 and PPL 2-5 ) for the imaging of Ab plaques. 12 These imaging agents consisted of a 1,4,7triazacylononane (TACN) or 2,11-diaza [3.3](2,6)-pyridinophane (PP) ligands conjugated to 2-phenyl-benzothiazole, which resembles the well-known Ab-binding dye Thioflavin T (ThT) (Fig. 5).…”

“…More recently, Pigge and co-workers reported a series of oligothiophene benzothiazole-based tetraarylethylene (TAE) Re(CO) 3 complexes (8)(9)(10)(11)(12)(13) and showed that these systems were capable of monitoring Ab aggregate formation in real time. 45 The benzothiazole TAE chelating ligands used in this study contain a different number of thiophene units, a variation that serves to modulate the photophysical properties and the binding affinities toward Ab fibrils.…”

Smart Chemiluminescence Probes and Dual-Amplification of Signal for Detection of Amyloid Beta Species in Alzheimer’s Disease Model

“…Although chemiluminescence has been intensively explored in many diseases such as cancers and diabetes, its applications in brain disorders including Alzheimer's disease (AD) is scarce. Ab plaques and neurofibrillary Tau tangles are the most pronounced and characteristic hallmarks of Alzheimer's disease (AD) [21][22][23] , and several imaging methods been widely applied in preclinical and clinical studies [24][25][26][27][28][29][30][31][32][33][34][35][36][37] . Optical imaging, including NIRF imaging and two-photon imaging, are the most used methods for preclinical investigations of fundamental pathological questions and for therapy monitoring in drug development.…”