Synthesis and Evaluation of Macrocyclic Gadolinium Chelates as Hepatospecific MRI Agents

Abstract

X-ray computed tomography (CT) is generally employed as the imaging modality of choice for the detection and staging of liver disease and focal hepatic lesions. However, the use of radiation and the relatively low resolution obtainable due to the lack of well-tolerated contrast agents that could specifically target the liver are disadvantageous in the clinic. Magnetic resonance imaging (MRI) offers high resolution and sensitivity, but general-purpose MRI contrast agents undergo almost exclusive renal and very little hepatobiliary excretion ( 1 Tweedle MT Relaxation agents in NMR imaging. in: Bunzli JCG Choppin GR Lanthanide probes in life, chemical and earth science. Elsevier, Amsterdam, The Netherlands1989: 127-179 Google Scholar , 2 Kumar K Macrocyclic polyaminocarboxylate complexes of Gd(M) as magnetic resonance imaging contrast agents. J Alloys Compd. 1997; 249: 163-172 Crossref Scopus (33) Google Scholar ). Also problematic is that the rapid clearance of extracellular space (ECS) MRI agents from the extracellular space provides a short time window for imaging ( 3 Weinmann HJ Brasch RC Press WR Wesby GE Characteristics of gadolinium-DTPA complex: a potential NMR contrast agent. AJR Am J Roentgenol. 1984; 142: 619-624 Crossref PubMed Scopus (1130) Google Scholar ). An MRI contrast agent that provides sustained enhancement of normal hepatic tissue due to uptake by the hepatic parenchyma and increased relaxivity in hepatic tissue vs that in blood would be superior for differentiation of normal hepatic tissue from benign masses or metastatic lesions. Hepatic uptake and excretion of lipophilic compounds, particularly anions, is a high-flux process and has been exploited in the design of hepatobiliary radiographic and radiopharmaceutical imaging agents ( 4 Nunn AD Loberg MD Conley RA A structure-distribution-relationship approach leading to the development of technetium-99m-labeled mebrofenin: an improved cholescintigraphic agent. J Nucl Med. 1983; 24: 423-430 PubMed Google Scholar , 5 Smith RL The excretory function of bile. Chapman and Hall, London, England1973: 31-33 Google Scholar ). We reasoned that it might be possible to employ such functionality in a compact, synthetically accessible design to obtain hepatospecific MRI contrast agents ( 6 Clement O Siauve N Lewin M de Kerviler E Cuenod CA Frija G Contrast agents in magnetic resonance imaging of the liver: present and future. Biomed Pharmacother. 1998; 52: 51-58 Crossref PubMed Scopus (32) Google Scholar ). The goal of this work was to prepare and evaluate the water solubility, biodistribution, hepatobiliary clearance, and acute tolerance of macrocyclic gadolinium chelates (Fig 1) as potential hepatospecific MRI agents. Secondary evaluation of the compound displaying the optimum combined set of properties would then be conducted, employing tissue relaxivity measurements and in vivo hepatobiliary MRI.