A Gd3+-Based Magnetic Resonance Imaging Contrast Agent Sensitive to β-Galactosidase Activity Utilizing a Receptor-Induced Magnetization Enhancement (RIME) Phenomenon
Kenjiro Hanaoka Dr.
Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan, Fax: (+81) 3-5841-4855
Search for more papers by this authorKazuya Kikuchi Prof. Dr.
Department of Materials and Life Sciences, Graduate School of Engineering, Osaka University, 2-1 Yamada-oka, Suita City, Osaka 565-0871, Japan
Search for more papers by this authorTakuya Terai
Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan, Fax: (+81) 3-5841-4855
Search for more papers by this authorToru Komatsu
Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan, Fax: (+81) 3-5841-4855
Search for more papers by this authorTetsuo Nagano Prof. Dr.
Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan, Fax: (+81) 3-5841-4855
Search for more papers by this authorKenjiro Hanaoka Dr.
Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan, Fax: (+81) 3-5841-4855
Search for more papers by this authorKazuya Kikuchi Prof. Dr.
Department of Materials and Life Sciences, Graduate School of Engineering, Osaka University, 2-1 Yamada-oka, Suita City, Osaka 565-0871, Japan
Search for more papers by this authorTakuya Terai
Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan, Fax: (+81) 3-5841-4855
Search for more papers by this authorToru Komatsu
Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan, Fax: (+81) 3-5841-4855
Search for more papers by this authorTetsuo Nagano Prof. Dr.
Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan, Fax: (+81) 3-5841-4855
Search for more papers by this authorGraphical Abstract
Monitoring β-galactosidase-activity: A novel β-galactosidase-activated MRI contrast agent, 1, was developed which is based on the receptor-induced magnetization enhancement (RIME) approach. The compound 1 exhibits an increase in the r1 relaxivity in response to β-galactosidase activity by binding to the macromolecule, human serum albumin (HSA) (see picture). The binding of an MRI contrast agent to a macromolecule substantially slows molecular rotation of the Gd3+ complex.
Abstract
Magnetic resonance imaging (MRI) permits noninvasive three-dimensional imaging of opaque organisms. Gadolinium (Gd3+) complexes have become important imaging tools as MRI contrast agents for MRI studies, though most of them are nonspecific and report solely on anatomy. Recently, MRI contrast agents have been reported whose ability to relax water protons is triggered or greatly enhanced by recognition of a particular biomolecule. This new class of MRI contrast agents could open up the possibility of reporting on the physiological state or metabolic activity deep within living specimens. One possible strategy for this purpose is to utilize the increase in the longitudinal water proton r1 relaxivity that occurs upon slowing the molecular rotation of a small paramagnetic complex, a phenomenon which is known as receptor-induced magnetization enhancement (RIME), by either binding to a macromolecule or polymerization of the agent itself. Here we describe the design and synthesis of a novel β-galactosidase-activated MRI contrast agent, the Gd3+ complex [Gd-5], by using the RIME approach. β-Galactosidase is commonly used as a marker gene to monitor gene expression. This newly synthesized compound exhibited a 57 % increase in the r1 relaxivity in phosphate-buffered saline (PBS) with 4.5 % w/v human serum albumin (HSA) in the presence of β-galactosidase. Detailed investigations revealed that RIME is the dominant factor in this increase of the observed r1 relaxivity, based on analysis of Gd3+ complexes [Gd-5] and [Gd-8], which is generated from [Gd-5] by the activity of β-galactosidase, and spectroscopic analysis of their corresponding Tb3+ complexes, [Tb-5] and [Tb-8].
Supporting Information
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