Synthesis and In Vitro and In Vivo Evaluation of 18F-Labeled Positron Emission Tomography Tracers for Imaging Aβ Plaques

Accurate quantification of amyloid beta (Aβ) plaques is an important indicator for Alzheimer's disease diagnosis and treatment. For this purpose, new highly sensitive Aβ tracers were designed by regulating the position and number of nitrogen atoms. A series of derivatives of florbetapir (AV45) containing different numbers and positions of N atoms were synthesized and evaluated for in vitro affinity and in vivo biodistribution. Preliminary study results showed that [¹⁸F]BIBD-124 and [¹⁸F]BIBD-127 had better clearance rates and less in vivo defluorination than AV45 in ICR (ICR = Institute of Cancer Research) mice. Autoradiography and molecular docking indicated that the binding sites of [¹⁸F]BIBD-124/127 were similar to that of [¹⁸F]AV45. Micro-positron emission tomography-computed tomography imaging further demonstrated that [¹⁸F]BIBD-124 could monitor Aβ plaques similar to [¹⁸F]AV45. Besides, the imaging contrast of [¹⁸F]BIBD-124 is better than that of [¹⁸F]AV45. Mass spectrometric metabolic analysis showed that BIBD-124 was less demethylated than AV45 without subsequent acetylation, which might explain its less non-specific uptake and higher imaging contrast. Gauss calculations further confirmed that the introduction of N5 in [¹⁸F]BIBD-124 decreased demethylation. Considering imaging contrast and in vivo defluorination, [¹⁸F]BIBD-124 is expected to be a promising radiotracer of Aβ plaques for further clinical trials.

Alzheimer’s disease; Aβ plaques; [18F]BIBD-124; positron emission tomography; tracer.