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

This report describes the evaluation of a series of novel cationic 99mTc-nitrido complexes, [99mTcN(DTC)(PNP)]+ (DTC=crown ether-containing dithiocarbamates; PNP=bisphosphine), as potential radiotracers for myocardial perfusion imaging. Synthesis of cationic 99mTc-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 99mTc 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 99mTc-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 [99mTcN(L2)(L6)]+ and [99mTcN(L4)(L6)]+ show heart/liver ratios four to five times better than that of 99mTc-sestamibi due to their much faster liver clearance. Their heart uptake and heart/liver ratio are comparable to that of 99mTcN-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 99mTc-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 99mTc-nitrido complexes. It is the combination of the appropriate DTCs and bisphosphines that results in cationic 99mTc-nitrido complexes with high heart uptake and fast clearance from the liver at the same time. The fast liver clearance of [99mTcN(L2)(L6)]+ and [99mTcN(L4)(L6)]+ suggests that they might be used to obtain clinically useful images as early as 30 min postinjection. [99mTcN(L2)(L6)]+ and [99mTcN(L4)(L6)]+ are very promising candidates for further evaluation in more extensive preclinical animal models.