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

• Published in: Nuclear medicine and biology 2000-02, Vol.27 (2), p.207-214
• Main Authors: Vanbilloen, Hubert P, Cleynhens, Bernard J, Verbruggen, Alfons M
• Format: Article
• Language: English
• Subjects: 99mTc-ECC; 99mTc-L; Biological and medical sciences; Contrast media. Radiopharmaceuticals; Isomers; L-EC; Medical sciences; Pharmacology. Drug treatments; Renal tracer agents; Technetium-99m labeled ethylenecysteamine cysteine
• ISSN: 0969-8051; 1872-9614
• DOI: 10.1016/S0969-8051(99)00092-X

A few years ago 99mTc-ethylenedicysteine ( 99mTc- L,L-EC) had been proposed as an interesting substitute for technetium-99m labeled mercaptoacetyltriglycine (MAG3) as renal function tracer agent. It possesses in its structure two carboxylate functions and is in this respect different from other renal tracers such as 99mTc- N,N′-bis-(mercaptoacetyl)-2,3-diaminopropionate ( 99mTc-CO 2DADS), 99mTc-MAG3, and Hippuran, which have only one carboxylic group. To study whether both carboxylic acid groups of 99mTc- L,L-EC contribute to the efficient renal handling of this compound we synthesized and biologically evaluated the technetium-99m labeled isomers of L- and D-ethylenecysteamine cysteine (ECC), the mono-acid derivative of 99mTc- L,L-EC. Labeling of L-ECC or D-ECC with 99mTc using a direct or exchange labeling method yields for each of them two diastereomeric 99mTc complexes (A and B, in the order of elution during reversed phase high performance liquid chromatography) in relative amounts depending on the pH during labeling. In mice, all four isomers of 99mTc-ECC ( LA, LB, DA, and DB) are cleared rapidly from the blood, mainly by the renal system. The isomers LB and DB show the most efficient renal handling, but none of the mono-acid derivatives has a urinary excretion rate as high as that of 99mTc- L,L-EC. The renal handling of the isomers of 99mTc-ECC is partly due to tubular secretion because the urinary excretion of these compounds is significantly lower in mice pretreated with probenecid. In the baboon, isomers DA and DB show a plasma clearance comparable to that of 99mTc- L,L-EC. The plasma clearance of isomers LA and LB is lower but still comparable to or higher than that of 99mTc-MAG3. In a human volunteer, isomer DB shows a plasma clearance rate only slightly lower than that of 99mTc- L,L-EC. Thus, it appears that the presence of one carboxylate in 99mTc-EC-like compounds can be sufficient for efficient renal handling. However, it is also evident that the configuration at the chiral carbon atom and the orientation of the oxotechnetium core determine in a significant way the biological characteristics.