Synthesis and biological evaluation of the four isomers of technetium-99m labeled ethylenecysteamine cysteine (Tc-99m-ECC), the mono-acid derivative of Tc-99m-L,L-ethylenedicysteine

A few years ago Tc-99m-ethylenedicysteine (Tc-99m-L,L-EC) had been proposed as an interesting substitute for technetium-99m labeled mercaptoacetyltrig lycine (MAG3) as renal function tracer agent. It possesses in its structure two carboxylate functions and is in this respect different from other rena l tracers such as Tc-99m-N,N'-bis-(mercaptoacetyl)-2,3-diaminopropionate (T c-99m-CO2,DADS), Tc-99m-MAG3, and Hippuran, which have only one carboxylic group. To study whether both carboxylic acid groups of Tc-99m-L,L-EC contri bute to the efficient renal handling of this compound we synthesized and bi ologically evaluated the technetium-99m labeled isomers of L- and D-ethylen ecysteamine cysteine (ECC), the mono-acid derivative of Tc-99m-L,L-EC. Labe ling of L-ECC or D-ECC with Tc-99m using a direct or exchange labeling meth od yields for each of them two diastereomeric Tc-99m complexes (A and B, in the order of elution during reversed phase high performance liquid chromat ography) in relative amounts depending on the pH during labeling. In mice, all four isomers of Tc-99m-ECC (LA, LB, DA, and DB) are cleared rapidly fro m the blood, mainly by the renal system. The isomers LB and DB show the mos t efficient renal handling, but none of the mono-acid derivatives has a uri nary excretion rate as high as that of Tc-99m-L,L-EC. The renal handling of the isomers of Tc-99m-ECC is partly due to tubular secretion because the u rinary excretion of these compounds is significantly lower in mice pretreat ed with probenecid. In the baboon, isomers DA and DB show a plasma clearanc e comparable to that of Tc-99m-L,L-EC. The plasma clearance of isomers LA a nd LB is lower but still comparable to or higher than that of Tc-99m-MAG3. In a human volunteer, isomer DB shows a plasma clearance rate only slightly lower than that of Tc-99m-L,L-EC. Thus, it appears that the presence of on e carboxylate in Tc-99m-EC-like compounds can be sufficient for efficient r enal handling. However, it is also evident that the configuration at the ch iral carbon atom and the orientation of the oxotechnetium core determine in a significant way the biological characteristics. NUCL MED BIOL 27;2:207-2 14, 2000. (C) 2000 Elsevier Science Inc, All rights reserved.