Evaluation of novel cationic 99mTc-nitrido complexes as radiopharmaceuticals for heart imaging: improving liver clearance with crown ether groups

Abstract

This report describes the evaluation of a series of novel cationic (99m)Tc-nitrido complexes, [(99m)TcN(DTC)(PNP)]+ (DTC = crown ether-containing dithiocarbamates; PNP = bisphosphine), as potential radiotracers for myocardial perfusion imaging. Synthesis of cationic (99m)Tc-nitrido complexes was accomplished in two steps according to literature methods. Biodistribution studies were performed in rats. Planar images of Sprague-Dawley rats administered with 15+/-2 MBq of cationic (99m)Tc radiotracer were obtained using a PhoGama large field-of-view Anger camera. Samples from both urine and feces were analyzed by a reversed-phase radio-HPLC method. Results from biodistribution studies showed that most of the cationic (99m)Tc-nitrido complexes have a high initial heart uptake with a long myocardial retention. They also show a rapid clearance from the liver and lungs. Cationic complexes [(99m)TcN(L2)(L6)]+ and [(99m)TcN(L4)(L6)]+ show heart/liver ratios four to five times better than that of (99m)Tc-sestamibi due to their much faster liver clearance. Their heart uptake and heart/liver ratio are comparable to that of (99m)TcN-DBODC5 within the experimental error. These findings have been confirmed by the results from imaging studies. Radio-HPLC analysis of urine and feces samples indicated that there was very little metabolism of cationic (99m)Tc-nitrido complexes in rats under anesthesia. The key finding of this study is that lipophilicity remains the most important factor affecting both heart uptake and target-to-background (T/B) ratios. Crown ethers are very useful functional groups to improve the liver clearance of cationic (99m)Tc-nitrido complexes. It is the combination of the appropriate DTCs and bisphosphines that results in cationic (99m)Tc-nitrido complexes with high heart uptake and fast clearance from the liver at the same time. The fast liver clearance of [(99m)TcN(L2)(L6)]+ and [(99m)TcN(L4)(L6)]+ suggests that they might be used to obtain clinically useful images as early as 30 min postinjection. [(99m)TcN(L2)(L6)]+ and [(99m)TcN(L4)(L6)]+ are very promising candidates for further evaluation in more extensive preclinical animal models.