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.
Department of Molecular Imaging and Radiotherapy, Graduate School of Pharmaceutical Sciences, Chiba University, Japan.
Tomoya
T
Uehara
Miho
M
Koike
Hideo
H
Nakata
Shigehiko
S
Miyamoto
Shoji
S
Motoishi
Kazuyuki
K
Hashimoto
Naoto
N
Oku
Morio
M
Nakayama
Yasushi
Y
Arano
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D008297:Male; D051379:Mice; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000378:metabolism* / Q000493:pharmacokinetics; D014018:Tissue Distribution
D009942:Organometallic Compounds; C116454:cyclopentadienyl tricarbonyl rhenium; C517413:tricarbonyl(cyclopentadienylcarbonate)rhenium