Multimodal MRI contrast agents

Abstract

The advent of powerful new imaging tools such as confocal and two-photon microscopy, MRI, PET, SPECT, and ultrasound have provided scientists and clinicians with the ability to acquire in vivo images of anatomy and physiology in whole animals and humans [1–3]. Each of these in vivo imaging techniques possesses unique strengths and weaknesses with varying spatial and temporal resolution limits [4]. Further, the development of sophisticated reporter probes for cell tracking, gene expression, and gene monitoring therapeutic paradigms is rapidly changing the way these techniques are being applied. For example, advances in optical microscopy have revolutionized the way living cells and intact tissues are studied [5]. As a result, cellular events, biochemical processes, and tissue morphogenesis can be followed in developing embryos at submicron resolution. MRI employs nonionizing radiation and has become an integral tool in clinical radiology, and more recently in experimental settings [6–8]. The intensity of the signal in each voxel is dependent on several intrinsic parameters, such as the proton density, longitudinal (R1) and transverse (R2) NMR relaxation rates, and extrinsic parameters, such as magnetic field strength, pulse sequence, and the presence of contrast agents (CAs). CAs for a variety of imaging methods have been in use for decades in diagnostic radiology and developmental biology [9–13]. The application of these CAs is well documented and the fundamental chemical principles for the synthesis and characterization of these complexes are known [14–16]. A rapidly growing body of literature documents the clinical effectiveness of paramagnetic CAs [17–19]. Currently, eight such CAs are in clinical use or clinical trials and more than 30% of all clinical MRI examinations employ CAs [20]. Paramagnetic metal ions, as a result of their unpaired electrons, act as potent relaxation-enhancement agents and decrease the T1 and T2 relaxation times of nearby spins [21]. Some paramagnetic ions decrease T1 without causing substantial line broadening [T1 agents; e.g., Gd(III)], while others induce drastic line broadening (T2 agents; e.g., superparamagnetic iron oxide) [22]. The lanthanide ion Gd(III) has generally been chosen as the metal ion for CAs because it has a high magnetic moment (l = 63 lB ) and a symmetric electronic ground state (S) [23]. Transition metal ions such as high-spin Mn(II) and Fe(III) are candidates owing to their high magnetic moments. The mechanism of T1 relaxation is generally a through-space dipole–dipole interaction between the unpaired electrons of the paramagnetic metal ion and the protons of coordinated or diffusing water molecules. The longitudinal and transverse relaxation rates (Ri) of a CA solution are proportional to the CA’s relaxivity rip (Eq. 1) [20, 23]: