In vivo recognition of cyclopentadienyltricarbonylrhenium (CpTR) derivatives

• Published in: Nuclear medicine and biology 2003-04, Vol.30 (3), p.327-334
• Main Authors: Uehara, Tomoya, Koike, Miho, Nakata, Hideo, Miyamoto, Shigehiko, Motoishi, Shoji, Hashimoto, Kazuyuki, Oku, Naoto, Nakayama, Morio, Arano, Yasushi
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Chromatography, High Pressure Liquid; cyclopentadienyltricarbonylmetal; glycine conjugation; Male; Medical sciences; metabolism; Mice; Organometallic Compounds - chemical synthesis; Organometallic Compounds - metabolism; Organometallic Compounds - pharmacokinetics; rhenium; Tissue Distribution
• ISSN: 0969-8051; 1872-9614
• DOI: 10.1016/S0969-8051(02)00437-7

In vivo metabolism of [ 188Re]tricarbonyl(carboxycyclopentadienyl)rhenium ([ 188Re]CpTR-COOH) and its glycine conjugate ([ 188Re]CpTR-Gly) was investigated to estimate the applicability of cyclopentadienyltricarbonylrhenium (CpTR) compounds to 186/188Re-labeling reagents for polypeptides and peptides. Both [ 188Re]CpTR derivatives were stable after incubation in a buffered-solution and in murine plasma at 37 °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 [ 188Re]CpTR-COOH was excreted by both hepatobiliary and urinary excretion, the majority of less lipophilic [ 188Re]CpTR-Gly was excreted by urinary excretion. In addition, while [ 188Re]CpTR-Gly was rapidly excreted into urine as its intact structure, [ 188Re]CpTR-COOH was metabolized to more hydrophilic compounds including its glycine conjugate, [ 188Re]CpTR-Gly. Renal excretion of [ 188Re]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 [ 186/188Re]CpTR-Gly from covalently conjugated 186/188Re-labeled polypeptides and peptides by the action of renal brush border enzymes would be useful to reduce renal radioactivity levels.