Impact of Bidentate Chelators on Lipophilicity, Stability, and Biodistribution Characteristics of Cationic 99mTc-Nitrido Complexes
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- 作者：Young-Seung Kim ; Zhengjie He ; Wen-Yuan Hsieh ; Shuang Liu
- 刊名：Bioconjugate Chemistry
- 出版年：2007
- 出版时间：May 2007
- 年：2007
- 卷：18
- 期：3
- 页码：929 - 936
- 全文大小：506K
- 年卷期：v.18,no.3(May 2007)
- ISSN：1520-4812
文摘
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 dihydrazidewith 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)]+ decomposesrapidly in the presence of cysteine (1 mg/mL) while [99mTcN(etma)(PNP6)]+ and [99mTcN(mpo)(PNP6)]+ remainstable for >6 h under the same conditions strongly suggests that thione-S donors in bidentate chelators increasethe solution stability of their cationic 99mTc-nitrido complexes. Biodistribution studies were performed on fourcationic 99mTc-nitrido complexes in Sprague-Dawley rats. [99mTcN(etma)(PNP5)]+ is of particular interest dueto 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 minpostinjection is almost identical that of 99mTcN-DBODC5 (6.01 ± 1.45), and is >2 times better than that of99mTc-sestamibi (2.90 ± 0.22). Results from metabolism studies show that [99mTcN(etma)(PNP5)]+ has no significantmetabolism 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 theheart as early as 30 min postinjection. [99mTcN(etma)(PNP5)]+ is a very promising candidate for more preclinicalevaluations in various animal models.
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)]+ decomposesrapidly in the presence of cysteine (1 mg/mL) while [99mTcN(etma)(PNP6)]+ and [99mTcN(mpo)(PNP6)]+ remainstable for >6 h under the same conditions strongly suggests that thione-S donors in bidentate chelators increasethe solution stability of their cationic 99mTc-nitrido complexes. Biodistribution studies were performed on fourcationic 99mTc-nitrido complexes in Sprague-Dawley rats. [99mTcN(etma)(PNP5)]+ is of particular interest dueto 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 minpostinjection is almost identical that of 99mTcN-DBODC5 (6.01 ± 1.45), and is >2 times better than that of99mTc-sestamibi (2.90 ± 0.22). Results from metabolism studies show that [99mTcN(etma)(PNP5)]+ has no significantmetabolism 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 theheart as early as 30 min postinjection. [99mTcN(etma)(PNP5)]+ is a very promising candidate for more preclinicalevaluations in various animal models.