Vol. 28, Issue 4, 418-422, April 2000

Disposition in Rats of N-Pyridinium-propyl-cyclam, N-Triethylammonium-propyl-cyclam, and N-[Triethylammonium]-3-propyl-[15]ane-N5, Potential Cartilage Imaging Agents

Jean-Claude Maurizis, Maryse Rapp, Colette Nicolas, Monique Ollier, Michel Verny, and Jean-Claude Madelmont

Institut National de la Santé et de la Recherche Médicale, Unité 484 (J.C.M., C.N., M.R., M.O., J.C.M.); and Université Blaise Pascal (M.V.), Clermont-Ferrand, France

Quaternary ammonium compounds are known to highly concentrate in articular cartilages after i.v. administration. This property was used to synthesize new potential radiodiagnostic agents for joint imaging. Pharmacokinetic study was performed in rats for three new compounds: N-pyridinium-propyl-cyclam (NPPC), N-triethylammonium-propyl-cyclam (NTPC), and N-[triethylammonium]-3-propyl-[15]ane-N5 (NTP 15-5). After i.v. administration, [³H]NPPC and [³H]NTPC highly and rapidly concentrated in articular cartilage, this uptake being followed by a single exponential decrease with half-lives of, respectively, 75 and 82 min. Except cartilage, only the kidney was highly labeled. After complexation of ^99mTc by NPPC, NTPC, and NTP 15-5, only ^99mTc-NTP 15-5 exhibited a high affinity for cartilage. On the other hand, the pharmacokinetic behavior of ^99mTc-NTPC and ^99mTc-NPPC was very different from those of their ³H-labeled analogs. Concentration in cartilaginous tissues was strongly diminished, and liver and bone were highly labeled. For all labeled species, the major route of excretion was urine, and HPLC analysis showed that [³H]NTPC and [³H]NPPC were excreted under their unchanged form. On the other hand, no ^99mTc-NTPC and ^99mTc-NPPC were found in the urine, the radioactivity being mainly due to free technetium, contrary to ^99mTc-NTP 15-5, which was excreted in the urine under the complexed form. These data can explain the striking differences observed between the three ^99mTc-labeled molecules, the lack of concentration of ^99mTc-NTPC, and ^99mTc-NPPC in cartilages in comparison with their ³H-labeled analogs due to an instability in vivo of these technetiated complexes.