Enhanced Positron Emission Tomography Imaging of β-Amyloid through Focused Ultrasound-Mediated Gallium-68 Radiotracer Delivery across the Blood-Brain Barrier.

Abstract

Focused ultrasound (FUS)-mediated blood-brain barrier (BBB) opening is an innovative approach for enhancing the delivery of central nervous system drugs. ⁶⁸Ga radiotracers are advantageous for imaging due to their ideal half-life and imaging properties; however, their limited ability to traverse the BBB constrains their application in brain imaging. This study investigates the application of FUS to selectively deliver the ⁶⁸Ga radiotracer, [⁶⁸Ga]STZL4110, into the hippocampus for β-amyloid positron emission tomography (PET) imaging in an Alzheimer's disease (AD) mouse model. The synthesis and radiolabeling of [⁶⁸Ga]STZL4110 were accomplished, demonstrating robust binding to β-amyloid, as validated by Thioflavin T assays and in vitro autoradiography with both wild-type (WT) and APP/PS1 AD mouse brain sections. Cavitation activity measurements confirmed effective and consistent BBB opening post-FUS treatment, ensuring targeted delivery without vascular damage, as supported by histological analysis. Quantitative PET imaging revealed the successful detection of β-amyloid deposition following FUS treatment. Initially, [⁶⁸Ga]STZL4110 showed a low volume of distribution in the right hippocampus of AD mice. FUS application significantly enhanced BBB permeability, leading to a 74% increase in [⁶⁸Ga]STZL4110 uptake in the targeted right hippocampus of APP/PS1 mice compared with the left hippocampus, whereas no significant change was observed in WT mice. These findings suggest that combining FUS with [⁶⁸Ga]STZL4110 could significantly enhance the sensitivity and specificity of ⁶⁸Ga PET imaging for β-amyloid. FUS-mediated PET imaging may potentially address the challenge of effective brain imaging with radiotracers that traditionally exhibit a low penetration of the BBB.