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. 2006 Nov-Dec;17(6):1499-507.
doi: 10.1021/bc060235l.

Impact of PKM linkers on biodistribution characteristics of the 99mTc-labeled cyclic RGDfK dimer

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

Impact of PKM linkers on biodistribution characteristics of the 99mTc-labeled cyclic RGDfK dimer

Shuang Liu et al. Bioconjug Chem. 2006 Nov-Dec.

Abstract

This report describes synthesis of three new cyclic RGDfK peptide conjugates, HYNIC-PKM-SU016 (PKM = E, K and PEG4) and in vivo evaluation of the impact of PKM linkers on biodistribution characteristics of their ternary ligand complexes [99mTc(HYNIC-PKM-SU016)1(tricine)(TPPTS)] in athymic nude mice bearing the MDA-MB-435 human breast cancer xenografts. Results from biodistribution studies show that PKM linkers have minimal impact on the integrin alphavbeta3 binding capability of radiotracers. Even though they have different charges under physiological conditions, all three linkers (E, K, and PEG4) are able to reduce the uptake of 99mTc-labeled E[c(RGDfK)]2 in blood, kidneys, liver, and lungs, and increase target-to-background (T/B) ratios at >30 min postinjection. E and K may have advantages over PEG4 due to a combination of relatively low liver uptake and high tumor/liver and tumor/lung ratios of ternary ligand complexes [99mTc(HYNIC-PKM-SU016)(tricine)(TPPTS)] (PKM = E and K).

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Figures

Figure 1
Figure 1
Structures of HYNIC-PKM-SU016 conjugates and their ternary ligand complexes [99mTc(HYNIC-PKM-SU016)(tricine)(TPPTS)] (PKM = E, K and PEG4).
Figure 2
Figure 2
Radio-HPLC chromatograms of [99mTc(HYNIC-E-SU016)(tricine)(TPPTS)] (top), [99mTc(HYNIC-K-SU016)(tricine)(TPPTS)] (middle), and [99mTc(HYNICPEG4- SU016)(tricine)(TPPTS)] (bottom) in the kit matrix.
Figure 3
Figure 3
Comparison of organ uptake (%ID/g) between [99mTc(HYNIC-SU016)(tricine)(TPPTS)], [99mTc(HYNIC-E-SU016)(tricine)(TPPTS)], [99mTc(HYNIC-K-SU016)(tricine)(TPPTS)], and [99mTc(HYNIC-PEG4-SU016)(tricine)(TPPTS)] in athymic nude mice bearing MDA-MB-435 human breast cancer xenografts.
Figure 4
Figure 4
Comparison of T/B ratios between [99mTc(HYNIC-SU016)(tricine)(TPPTS)], [99mTc(HYNIC-E-SU016)(tricine)(TPPTS)], [99mTc(HYNIC-KSu016)(tricine)(TPPTS)], and [99mTc(HYNIC-PEG4-SU016)(tricine)(TPPTS)] in athymic nude mice bearing MDA-MB-435 human breast cancer xenografts.
Figure 5
Figure 5
Radio-HPLC chromatograms of [99mTc(HYNIC-E-SU016)(tricine)(TPPTS)] (top), [99mTc(HYNIC-K-SU016)(tricine)(TPPTS)] (middle), and [99mTc(HYNICPEG4-SU016)(tricine)(TPPTS)] (bottom) in the urine at 120 min postinjection. Each tumor-bearing mouse was administered with 100 – 120 µCi of radiotracer. Two tumor-bearing mice were used for each radiotracer.
Chart I
Chart I
Synthesis of HYNIC-Conjugated Cyclic RGDfK Conjugates
Chart II
Chart II
Synthesis of Ternary Ligand 99mTc Complexes
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