In vivo recognition of cyclopentadienyltricarbonylrhenium (CpTR) derivatives

In vivo metabolism of [(188)Re]tricarbonyl(carboxycyclopentadienyl)rhenium ([(188)Re]CpTR-COOH) and its glycine conjugate ([(188)Re]CpTR-Gly) was investigated to estimate the applicability of cyclopentadienyltricarbonylrhenium (CpTR) compounds to (186/188)Re-labeling reagents for polypeptides and peptides. Both [(188)Re]CpTR derivatives were stable after incubation in a buffered-solution and in murine plasma at 37 degrees C for 6 h. Plasma protein binding was hardly observed with the two derivatives. However, different biodistribution and metabolic fates were observed with the two CpTR derivatives. While more lipophilic [(188)Re]CpTR-COOH was excreted by both hepatobiliary and urinary excretion, the majority of less lipophilic [(188)Re]CpTR-Gly was excreted by urinary excretion. In addition, while [(188)Re]CpTR-Gly was rapidly excreted into urine as its intact structure, [(188)Re]CpTR-COOH was metabolized to more hydrophilic compounds including its glycine conjugate, [(188)Re]CpTR-Gly. Renal excretion of [(188)Re]CpTR-Gly was significantly reduced in probenecid retreated mice. The present studies reinforced that CpTR core remained stable under biological environment. CpTR-COOH was partially recognized as an aromatic acid and was metabolized as such. However, glycine conjugation rendered CpTR-COOH hydrophilic enough to be excreted into urine without further metabolism. These findings suggested that radiolabeling reagents that liberate [(186/188)Re]CpTR-Gly from covalently conjugated (186/188)Re-labeled polypeptides and peptides by the action of renal brush border enzymes would be useful to reduce renal radioactivity levels.