Basic Design and Synthesis of Sulfonated Contrast Agents for Magnetic Resonance Imaging Based on Gadolinium Complexes

Abstract

Magnetic resonance imaging (MRI) is a powerful noninvasive diagnostic technique that can differentiate normal tissue from diseased tissue and lesions. Magnetic resonance angiography (MRA) is a specialized MRI technique of gradually increasing importance that can provide angiography and can assess angiogenesis, blood volume and blood flow. [1][2][3][4] Various contrast agents based on gadolinium ion (Gd 3+ ) complexes have been developed to enhance the MRI signal intensity and to improve the contrast-to-noise ratio in regions of interest by shortening the longitudinal relaxation time (T1) of water protons. However, the presently clinically-used contrast agents, such as Gd(DTPA) (gadolinium-diethylenetriaminepentaacetic acid: Magnevist ® ) and Gd(EOB-DTPA) (gadolinium-(4S)-4-(4-ethoxybenzyl)-3,6,9-tris(carboxylatomethyl)-3,6,9-triazaundecanedioic aciddisodium salt: Eovist ® ), are not suitable as blood pool contrast agents for the MRA technique due to their short plasma halflives caused by rapid elimination from the kidney and the liver, respectively, 5-9 and/or the characteristic of free extravasation into background muscles, 10 resulting in a rapid decrease of the contrast-to-noise ratio in blood vessels.For routine T1-weighted MRA examinations, the blood pool contrast agent is desired to have a long plasma half-life, and to be retained selectively in the intravascular space in order to obtain a high contrast-to-noise ratio, and to eliminate completely from the blood after MRI examinations. Macromolecular MRI contrast agents based on albumin, 11,12 polymers 13-17 and dendrimers [18][19][20] have been developed as blood pool contrast agents, and were shown to have long plasma half-lives with a high relaxivity, which is a parameter representing the ability to act as a contrast agent. However, these macromolecular contrast agents have some limitations for clinical applications: (i) the possibility of eliciting an immune response due to the use of proteins and large molecules and/or (ii) significantly slow elimination from the body and subsequent metabolism, which could lead to the release of toxic by-products including free Gd 3+ . 14,[21][22][23][24][25] To address such limitations and potentials of these macromolecular MRI contrast agents, low molecular-weight gadolinium complexes have been chemically designed to bind noncovalently to substances like plasma proteins. 8,[26][27][28][29][30] As an example, due to its specific structure, MS-325 (Vasovist ® ) can bind strongly but noncovalently to human serum albumin (HSA), resulting in an extension of the plasma half-life (23.1 ± 2.9 min in rats 31 and approximately 2 -3 h in primates) 31 and an appropriate elimination from the organism. 32,33This long plasma half-life of MS-325 allows MRA imaging with substantial contrast-to-noise ratio to be performed for approximately 50 min in humans after administration. 34 As a result, the long imaging window permits multiple vascular stations or the same vascular bed to be scanned several times after a single injection, resul...

Synthesis and Physicochemical Characterization of Carbon Backbone Modified [Gd(TTDA)(H2O)]2− Derivatives

“…The lipophilic residue facilitates noncovalent interaction of MS-325 to the lipid binding sites of HSA and significantly augments its plasma half-life. Hydrophilic−lipophilic balance (HLB) of the Gd(III) complex is a vital factor controlling the plasma half-life and elimination from the organism . To augment the lipophilicity of the [Gd(TTDA)(H 2 O)] 2− , we introduce lipophilic residues such as cyclobutyl and benzyl groups on the carbon backbone.…”

“…Hydrophilic-lipophilic balance (HLB) of the Gd(III) complex is a vital factor controlling the plasma half-life and elimination from the organism. 74 To augment the lipophilicity of the [Gd(TTDA)(H 2 O)] 2-, we introduce lipophilic residues such as cyclobutyl and benzyl groups on the carbon backbone. The octanol-water distribution ratio, K O/W , is the accepted physicochemical property measuring the hydrophobicity of Gd(III) complexes.…”

Gd(iii) chelates for MRI contrast agents: from high relaxivity to “smart”, from blood pool to blood–brain barrier permeable

“…16). 127 The lipophilicity and the hydrophilicity of the Gd(III) complexes were investigated in order to increase the plasma half-life by binding to human serum albumin. The results showed that KMR-Sulfo5 has a relaxivity r 1 of 5.9 mM À1 s À1 and a long plasma half-life of 25.7 min.…”