Insights into the failure of the potential, neutral myocardial imaging agent TcN-NOET: physicochemical identification of by-products and degradation species

Introduction: The neutral complex [99mTc(N)(NOEt)2], often referred to as TcN-NOET [NOEt=N-ethoxy,N-ethyldithiocarbamate(1−)], was proposed several years ago as a myocardial imaging agent. Despite some favorable clinical properties evidenced during phase I and phase II studies, the overall results of the European and American phase III clinical studies have been judged insufficient for a successful approval process by the regulatory agencies. Methods: Non-carrier-added and carrier-added experiments using short-lived 99mTc and long-lived 99gTc have been utilized to prepare a series of bis-substituted [Tc(N)(DTC)2] complexes [DTC=dithiocarbamate(1−)]. They have been purified by means of chromatographic techniques (high-performance liquid chromatography and thin-layer chromatography) and identified via double detection (UV-vis and radiometry) by comparison with authenticated samples of 99gTc compounds prepared by conventional coordination chemistry procedures. Results: The molecular structure of the lipophilic, neutral complex cis-[Tc(N)(NOEt)2] has been assigned by comparison with similar nitrido-Tc(V) complexes already reported in the literature. Novel bis-substituted nitrido-Tc complexes containing hydrolyzed portions of coordinated NOEt, namely, N-ethyldithiocarbamate [NHEt(1−)] and N-hydroxy, N-ethyldithiocarbamate [NOHEt(1−)], have been prepared and characterized by means of multinuclear nuclear magnetic resonance spectroscopy and mass spectrometry. Conclusions: Despite the identification of these "hydrolyzed" species, it is still unclear whether the failure to reach the clinical goal of the perfusion tracer [99mTc(N)(NOEt)2] is related to the degradation processes evidenced in this study or is the result of the mediocre imaging properties of the tracer.