Synthesis and biological characteristics of the Technetium‐99m triamide derivatives of mercaptoacetyltriglycine (MAG₃)

Abstract

SummaryA number of MAG 3 -derivatives, containing the three-amide functions modified by inverting the sequence -CO-NH-to -NH-CO-in the firstand/or second-amide functions, have been labelled with 99m Tc in order to study the renal characteristics of the resulting MAG 3 -derivatives versus the reference 99m Tc-MAG 3 . The 99m Tc-MAG 3 -derivatives displayed HPLC-profiles similar to that of 99m Tc-MAG 3 . Furthermore, in mice they exhibited biological behaviour comparable or even superior to 99m Tc-MAG 3 , which indicates that the sequence of the first-and/or second-amide bond in 99m Tc-MAG 3 affects the biological behaviour only to a limited degree. However, in baboon the plasma clearance of the 99m Tc-MAG 3 -derivatives was relatively slower than 99m Tc-MAG 3 , which underlines the inter-species variability.

Synthesis, radiolabelling characteristics and biological evaluation of the derivatives of mercaptoacetyltriglycine

“…D-alanine was converted (by reacting with benzyl chloroformate under alkaline conditions) to the carbobenzyloxy derivative 1D, which was reacted with S-benzylcysteamine hydrochloride (prepared from 2-aminoethanethiol hydrochloride and benzyl chloride in liquid ammonia) [4,9] in the presence of 1-hydroxybenzotriazole (HOBT)/1,3-dicyclohexylcarbodiimide (DCC) and triethylamine (Et 3 N) to give N-carbobenzyloxy-D-alanyl-S-benzylcysteamine 2D. Deprotection of CBZ-group with HBr/ HOAc gave the hydrobromide 3D, which was then reacted with ethyloxalyl chloride in the presence of diisopropylethylamine (DIPEA) to provide N-ethyloxalyl-D-alanyl-S-benzylcysteamine 4D.…”

“…Coupling of the intermediate L-alanyl-S-benzylcysteamine hydrobromide 3L (prepared in the same way as described for 3D) with N-hydroxysuccinimidyl oxalylglycine ethyl ester [4] (obtained by the reaction of tertbutyl alcohol with oxalyl chloride and glycine ethyl ester hydrochloride followed by the removal of tert-butyl group with TFA and activation of the resulting acid in the presence of NHS/DCC) gave the ethyl ester derivative 7L, which was hydrolyzed with base to the corresponding acid 6L in an overall yield of 11%.…”

“…To this DCC (12.40 g, 60 mmol) dissolved in CH 2 Cl 2 (10 mL) was added slowly. After 30 min, S-benzylcysteamine hydrochloride (12.21 g, 60 mmol) [4,9] was added followed by Et 3 N (9.8 mL, 70 mmol) and stirring was continued overnight. The precipitated dicyclohexylurea was removed by filtration.…”

“…In the past 15 years, a number of derivatives of 99m Tc-MAG 3 with slight modifications in structure have been prepared and evaluated to develop an agent with improved renal characteristics [1][2][3][4][5][6][7]. The outcome is that a slight change in structure of MAG 3 may have significant effects on the routes and rates of excretion of 99m Tc-MAG 3 -like compounds [8].…”

“…We have shown previously that the inversion of the first and/or second amide bond in the 99m Tc-MAG 3 structure affects the biological behavior to a limited degree and can result in a derivative with slightly superior renal characteristics [4]. As an extension to this study, we have now synthesized a number of additional derivatives of 99m Tc-MAG 3 , which besides an inverted first and/or second amide bond contains a methyl or carboxyl substituent on the ligand backbone.…”