Impact of Bidentate Chelators on Lipophilicity, Stability, and Biodistribution Characteristics of Cationic 99mTc-Nitrido Complexes

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Abstract
This report describes synthesis and evaluation of novel cationic 99mTc-nitrido complexes, [99mTcN(L)(PNP)]+ (L = ma, ema, tma, etma and mpo; PNP = PNP5, PNP6, and L6), as potential radiotracers for heart imaging. Cationic complexes [99mTcN(L)(PNP)]+ were prepared in two steps. For example, reaction of succinic dihydrazide with 99mTcO4- in the presence of excess stannous chloride and PDTA resulted in the [99mTcN(PDTA)n] intermediate, which then reacted Hmpo and PNP6 at 100 °C for 10−15 min to give [99mTcN(mpo)(PNP6)]+ in >90% yield. It was found that bidentate chelators have a significant impact on lipophilicity, solution stability, biodistribution, and metabolic stability of cationic 99mTc-nitrido complexes. The fact that [99mTcN(ema)(PNP6)]+ decomposes rapidly in the presence of cysteine (1 mg/mL) while [99mTcN(etma)(PNP6)]+ and [99mTcN(mpo)(PNP6)]+ remain stable for >6 h under the same conditions strongly suggests that thione-S donors in bidentate chelators increase the solution stability of their cationic 99mTc-nitrido complexes. Biodistribution studies were performed on four cationic 99mTc-nitrido complexes in Sprague−Dawley rats. [99mTcN(etma)(PNP5)]+ is of particular interest due to its high initial heart uptake (1.81 ± 0.35 %ID/g at 5 min postinjection), and long myocardial retention (1.99 ± 0.47 %ID/g at 120 min postinjection). The heart/liver ratio of [99mTcN(etma)(PNP5)]+ (6.06 ± 1.48) at 30 min postinjection is almost identical that of 99mTcN-DBODC5 (6.01 ± 1.45), and is >2 times better than that of 99mTc-sestamibi (2.90 ± 0.22). Results from metabolism studies show that [99mTcN(etma)(PNP5)]+ has no significant metabolism in the urine, but it does show significant metabolism in feces samples at 120 min postinjection. Planar imaging studies suggest that [99mTcN(etma)(PNP5)]+ might be able to give clinically useful images of the heart as early as 30 min postinjection. [99mTcN(etma)(PNP5)]+ is a very promising candidate for more preclinical evaluations in various animal models.