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We previously identified two new agents based on the [(99m)Tc(V)O](3+) core with renal clearances in human volunteers 30% higher than that of the widely used clinical tracer (99m)Tc-MAG3 (MAG3(5-) = penta-anion of mercaptoacetyltriglycine). However, renal agents with even higher clearances are needed. More recently, we changed our focus from the [(99m)Tc(V)O](3+) core to the discovery of superior tracers based on the fac-[(99m)Tc(I)(CO)3](+) core. Compared to (99m)Tc-MAG3, fac-[(99m)Tc(I)(CO)3(NTA)](2-) (NTA(3-) = trianion of nitrilotriacetic acid) holds great promise by virtue of its efficient renal clearance via tubular secretion and the absence of hepatobiliary elimination, even in patients with severely reduced renal function. We report here NMR, molecular (X-ray) structure, and solution data on fac-[Re(I)(CO)3(NTA)](2-) with a -CH2CO2(-) dangling monoanionic chain and on two fac-[Re(I)(CO)3(L)](-) analogues with either a -CH2CONH2 or a -CH2CH2OH dangling neutral chain. In these three fac-[Re(I)(CO)3(L)](n-) complexes, the fac-[Re(I)(CO)3(N(CH2CO2)2)](-) moiety is structurally similar and has similar electronic properties (as assessed by NMR data). In reported and ongoing studies, the two fac-[(99m)Tc(I)(CO)3(L)](-) analogues with these neutral dangling chains were found to have pharmacokinetic properties very similar to those of fac-[(99m)Tc(I)(CO)3(NTA)](2-). Therefore, we reach the unexpected conclusion that in fac-[(99m)Tc(I)(CO)3(L)](n-) agents, renal clearance is affected much more than anticipated by features of the core plus the chelate rings (the [(99m)Tc(I)(CO)3(N(CH2CO2)2)](-) moiety) than by the presence of a negatively charged dangling carboxylate chain.

The reaction of an aminopolycarboxylate ligand, aspartic-N-monoacetic acid (ASMA), with [Re(CO)3(H2O)3]+ was examined. The tridentate coordination of ASMA to this ReI tricarbonyl precursor yielded fac-Re(CO)3(ASMA) as a mixture of diastereomers. The chemistry is analogous to that of the TcI tricarbonyl complex, which yields fac-99mTc(CO)3(ASMA) under similar conditions. The formation, structure, and isomerization of fac-Re(CO)3(ASMA) products were characterized by HPLC, 1H NMR spectroscopy, and X-ray crystallography. The two major fac-Re(CO)3(ASMA) diastereomeric products each have a linear ONO coordination mode with two adjacent five-membered chelate rings, but they differ in the endo or exo orientation of the uncoordinated acetate group, in agreement with expectations based on previous studies. Conditions have been identified for the expedient isomerization of fac-Re(CO)3(ASMA) to a mixture consisting primarily of one major product. Because different isomeric species typically have different pharmacokinetic characteristics, these conditions may provide for the practical isolation of a single 99mTc(CO)3(ASMA) species, thus allowing the isolation of the isomer that has optimal imaging and pharmacokinetic characteristics. This information will aid in the design of future 99mTc radiopharmaceuticals.

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.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.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 (P0.05) than did (131)I-OIH and was better retained in the blood (P0.05).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.