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Fatty-acyl iminopolycarboxylates: lipophilic bifunctional contrast agents for NMR imaging
S K Kim1, G M Pohost, G A Elgavish
1Department of Medicine, University of Alabama, Birmingham 35294.
New fatty-acyl contrast agents, N3-2'-myristoyloxyethyl-N6-2'-hydroxyethyl-1, 8-dioxotriethylenetetraamine-N,N,N',N'-tetraacetic acid (MHE-DTTA) and N3,N6-bis(2'-myristoyloxyethyl)-1,8-dioxo- triethylenetetraamine-N,N,N',N'-tetraacetic acid (BME-DTTA) were prepared by sequential alkylation, acylation, and catalytic hydrogenation from bis(hydroxyethyl)-ethylenediamine with satisfactory yields (overall 36-46%). The 1:1 gadolinium complexes of the ligands MHE-DTTA and BME-DTTA were incorporated into liposomes and their relaxivities in vitro were determined. The relaxivities of both agents were similar and were greater than those of Gd3+ aquoion, Gd(EDTA), and Gd(DTPA) at both 0.23 T and 0.47 T. The relaxivities of these two agents increased from the lower to the higher magnetic field, indicating a positive field dependence. This is advantageous because of the widespread use of high-field (B0 greater than 0.5 T) NMR imaging instruments. Stability constants (log K) of Gd(MHE-DTTA) and Gd(BME-DTTA) were found to be 15.27 +/- 2.21 and 16.78 +/- 0.36, respectively. LD50 of both compounds was greater than 0.2 mmol/kg. These stabilities and lower limits of LD50 indicate the possible in vivo application of these agents.
New fatty-acyl contrast agents, N3-2'-myristoyloxyethyl-N6-2'-hydroxyethyl-1, 8-dioxotriethylenetetraamine-N,N,N',N'-tetraacetic acid (MHE-DTTA) and N3,N6-bis(2'-myristoyloxyethyl)-1,8-dioxo- triethylenetetraamine-N,N,N',N'-tetraacetic acid (BME-DTTA) were prepared by sequential alkylation, acylation, and catalytic hydrogenation from bis(hydroxyethyl)-ethylenediamine with satisfactory yields (overall 36-46%). The 1:1 gadolinium complexes of the ligands MHE-DTTA and BME-DTTA were incorporated into liposomes and their relaxivities in vitro were determined. The relaxivities of both agents were similar and were greater than those of Gd3+ aquoion, Gd(EDTA), and Gd(DTPA) at both 0.23 T and 0.47 T. The relaxivities of these two agents increased from the lower to the higher magnetic field, indicating a positive field dependence. This is advantageous because of the widespread use of high-field (B0 greater than 0.5 T) NMR imaging instruments. Stability constants (log K) of Gd(MHE-DTTA) and Gd(BME-DTTA) were found to be 15.27 +/- 2.21 and 16.78 +/- 0.36, respectively. LD50 of both compounds was greater than 0.2 mmol/kg. These stabilities and lower limits of LD50 indicate the possible in vivo application of these agents.