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. 2007 May-Jun;18(3):929-36.
doi: 10.1021/bc0603182. Epub 2007 Mar 13.

Impact of bidentate chelators on lipophilicity, stability, and biodistribution characteristics of cationic 99mTc-nitrido complexes

Young-Seung Kim  1 , Zhengjie He, Wen-Yuan Hsieh, Shuang Liu
Affiliations

Impact of bidentate chelators on lipophilicity, stability, and biodistribution characteristics of cationic 99mTc-nitrido complexes

Young-Seung Kim et al. Bioconjug Chem. 2007 May-Jun.

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 degrees 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.

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Figures

Figure 1
Figure 1
Bidentate chelators (Hma, Hema, Htma, Hetma, and Hmpo), bisphosphines (PNP5, PNP6 and L6), and their cationic 99mTc-nitrido complexes [99mTcN(L)(PNP)]+ (L = ma, ema, tma, etma and mpo; PNP = PNP5, PNP6 and L6).
Figure 2
Figure 2
Typical radio-HPLC chromatograms of [99mTcN(ma)(PNP6)]+ (top) and [99mTcN(ema)(PNP6)]+ (bottom).
Figure 3
Figure 3
Radio-HPLC chromatogram of the reaction mixture containing [99mTcN(ma)(PNP6)]+ (left) and [99mTcN(ema)(PNP6)]+ (right).
Figure 4
Figure 4
Radio-HPLC chromatogram of the reaction mixture containing [99mTcN(ma)(L6)]+ (left) and [99mTcN(ma)(PNP6)]+ (right). The radioimpurities (~20%) at 10 – 12 min are caused by the partial oxidation of PNP6.
Figure 5
Figure 5
Solution Stability data for [99mTcN(ema)(PNP6)]+, [99mTcN(etma)(PNP6)]+ and [99mTcN(mpo)(PNP6)]+.
Figure 6
Figure 6
Comparison of heart uptake (top) and heart/liver (bottom) ratios between [99mTcN(ema)(L6)]+, [99mTcN(tma)(L6)]+, [99mTcN(etma)(PNP5)]+, 99mTcN-DBODC5, 99mTc-Sestamibi, and [99mTcN(L4)(L6)]+.
Figure 7
Figure 7
Planar images of rats administered with ~ 500 μCi of [99mTcN(etma)(PNP5)]+, 99mTc-Sestamibi and 99mTcN-DBODC5. Arrows indicate the location of the heart, liver and salivary gland (as determined by ex-vivo gamma counting).
Figure 8
Figure 8
Radio-HPLC chromatograms of [99mTcN(etma)(PNP5)]+ in the kit matrix before injection (A), in the urine at 30 min p.i. (B), in the urine at 120 min p.i. (C), and in feces at 120 min p.i. (D). Each rat was administered with ~500 μCi of [99mTcN(etma)(PNP5)]+.
Scheme I
Scheme I
Synthesis of Cationic Complexes [99mTcN(L)(PNP)]+ (L = ma, ema, tma, etma, and mpo; PNP = PNP5, PNP6 and L6).
See this image and copyright information in PMC

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