MR-Guided Delivery of Hydrophilic Molecular Imaging Agents Across the Blood-Brain Barrier Through Focused Ultrasound.

Abstract

A wide variety of hydrophilic imaging and therapeutic agents are unable to gain access to the central nervous system (CNS) due to the blood-brain barrier (BBB). In particular, unless a particular transporter exists that may transport the agent across the BBB, most agents that are larger than 500Da or that are hydrophilic will be excluded by the BBB. Glutamate carboxypeptidase II (GCPII), also known as the prostate-specific membrane antigen (PSMA) in the periphery, has been implicated in various neuropsychiatric conditions. As all agents that target GCPII are hydrophilic and thereby excluded from the CNS, we used GCPII as a platform for demonstrating our MR-guided focused ultrasound (MRgFUS) technique for delivery of GCPII/PSMA-specific imaging agents to the brain. Female rats underwent MRgFUS-mediated opening of the BBB. After opening of the BBB, either a radio- or fluorescently labeled ureido-based ligand for GCPII/PSMA was administered intravenously. Brain uptake was assessed for 2-(3-{1-carboxy-5-[(6-[18F]fluoro-pyridine-3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid ([18F]DCFPyL) and YC-27, two compounds known to bind GCPII/PSMA with high affinity, using positron emission tomography (PET) and near-infrared fluorescence (NIRF) imaging, respectively. Specificity of ligand binding to GCPII/PSMA in the brain was determined with co-administration of a molar excess of ZJ-43, a compound of the same chemical class but different structure from either [18F]DCFPyL or YC-27, which competes for GCPII/PSMA binding. Dynamic PET imaging using [18F]DCFPyL demonstrated that target uptake reached a plateau by ∼1h after radiotracer administration, with target/background ratios continuing to increase throughout the course of imaging, from a ratio of ∼4:1 at 45min to ∼7:1 by 80min. NIRF imaging likewise demonstrated delivery of YC-27 to the brain, with clear visualization of tracer in the brain at 24h. Tissue uptake of both ligands was greatly diminished by ZJ-43 co-administration, establishing specificity of binding of each to GCPII/PSMA. On gross and histological examination, animals showed no evidence for hemorrhage or other deleterious consequences of MRgFUS. MRgFUS provided safe opening of the BBB to enable specific delivery of two hydrophilic agents to target tissues within the brain. This platform might facilitate imaging and therapy using a variety of agents that have heretofore been excluded from the CNS.