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Comparative Study
. 2012 Aug;53(8):1277-83.
doi: 10.2967/jnumed.111.102236. Epub 2012 Jun 20.

Preclinical evaluation of 99mTc(CO)3-aspartic-N-monoacetic acid, a renal radiotracer with pharmacokinetic properties comparable to 131I-o-iodohippurate

Affiliations
Comparative Study

Preclinical evaluation of 99mTc(CO)3-aspartic-N-monoacetic acid, a renal radiotracer with pharmacokinetic properties comparable to 131I-o-iodohippurate

Malgorzata Lipowska et al. J Nucl Med. 2012 Aug.

Abstract

In an ongoing effort to develop a renal tracer with pharmacokinetic properties comparable to p-aminohippurate and superior to those of both (99m)Tc-mercaptoacetyltriglycine and (131)I-o-iodohippurate ((131)I-OIH), we evaluated a new renal tricarbonyl radiotracer based on the aspartic-N-monoacetic acid (ASMA) ligand, (99m)Tc(CO)(3)(ASMA). The ASMA ligand features 2 carboxyl groups and an amine function for the coordination of the {(99m)Tc(CO)(3)}(+) core as well as a dangling carboxylate to facilitate rapid renal clearance.

Methods: rac-ASMA and l-ASMA were labeled with a (99m)Tc-tricarbonyl precursor, and radiochemical purity of the labeled products was determined by high-performance liquid chromatography. Using (131)I-OIH as an internal control, we evaluated biodistribution in normal rats with (99m)Tc(CO)(3)(ASMA) isomers and in rats with renal pedicle ligation with (99m)Tc(CO)(3)(rac-ASMA). Clearance studies were conducted in 4 additional rats. In vitro radiotracer stability was determined in phosphate-buffered saline, pH 7.4, and in challenge studies with cysteine and histidine. (99m)Tc(CO)(3)(ASMA) metabolites in urine were analyzed by high-performance liquid chromatography.

Results: Both (99m)Tc(CO)(3)(ASMA) preparations had greater than 99% radiochemical purity and were stable in phosphate-buffered saline, pH 7.4, for 24 h. Challenge studies on both revealed no significant displacement of the ligand. In normal rats, the percentage injected dose in urine at 10 and 60 min for both preparations averaged, respectively, 103% and 106% that of (131)I-OIH. The renal clearances of (99m)Tc(CO)(3)(rac-ASMA) and (131)I-OIH were comparable (P = 0.48). The tracer was excreted unchanged in the urine, proving its in vivo stability. In pedicle-ligated rats, (99m)Tc(CO)(3)(rac-ASMA) had less excretion into the bowel (P < 0.05) than did (131)I-OIH and was better retained in the blood (P < 0.05).

Conclusion: Both (99m)Tc(CO)(3)(ASMA) complexes have pharmacokinetic properties in rats comparable to or superior to those of (131)I-OIH, and human studies are warranted for their further evaluation.

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Figures

FIGURE 1
FIGURE 1
Structure of nitrilotriacetic acid (NTA) and aspartic-N-monoacetic acid (ASMA) ligands. The ellipse encloses the dangling carboxyl group and the asterisk indicates an asymmetric carbon.
FIGURE 2
FIGURE 2
Preparation of two diastereomers of 99mTc(CO)3(L-ASMA).
FIGURE 3
FIGURE 3
HPLC of 99mTc(CO)3(L-ASMA): labeling mixture (A), before injection (B), in urine at 15 min after injection (C), and UV-trace (254 nm) of Re(CO)3(L-ASMA) (D).
FIGURE 4
FIGURE 4
Biodistribution of 99mTc(CO)3(rac-ASMA) and 131I-OIH in normal rats at 10 min (A) and 60 min (B) after injection, and in rats with renal pedicle ligation at 60 min after injection (C), expressed as %ID per organ, blood and urine.

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