Impact of bifunctional chelators on biological properties of 111In-labeled cyclic peptide RGD dimers

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Abstract
The present study describes the synthesis and biological evaluation of 111In(DOTA-3P-RGD2) (DOTA = 1,4,7,10-tetraazacyclo-dodecane-1,4,7,10-tetraacetic acid; 3P-RGD2 = PEG4-E[PEG4-c(RGDfK)]2; PEG4 = 15-amino-4,7,10,13-tetraoxapentadecanoic acid), 111In(DTPA-3P-RGD2) (DTPA = diethylenetriaminepentaacetic acid) and 111In(DTPA-Bn-3P-RGD2) (DTPA-Bn = 2-(p-thioureidobenzyl)-diethylenetriaminepentaacetic acid) as potential radiotracers for imaging tumor integrin αvβ3 expression in athymic nude mice bearing U87MG glioma xenografts. The aim of the study is to assess the impact of the bifunctional chelator (BFC) (DOTA vs. DTPA or DTPA-Bn) on the biodistribution characteristics of the 111In-labeled 3P-RGD2. IC50 values of DOTA-3P-RGD2, DTPA-3P-RGD2 and DTPA-Bn-3P-RGD2 were determined to be 1.3 ± 0.2, 1.4 ± 0.3, 1.3 ± 0.3 nM, respectively, against 125I-c(RGDyK) bound to U87MG human glioma cells. Radiotracers were prepared by reacting 111InCl3 with the RGD peptide conjugates in NH4OAc buffer (100 mM, pH 5.5). For DOTA-3P-RGD2, successful radiolabeling could be completed by heating the reaction mixture at 100°C for 15–20 min. For DTPA-3P-RGD2 and DTPA-Bn-3P-RGD2, the radiolabeling was almost instantaneous at room temperature. The specific activity was ~50 mCi/mg (or ~100 mCi/μmol) for 111In(DOTA-3P-RGD2) and ~200 mCi/mg (or ~400 mCi/μmol) for 111In(DTPA-3P-RGD2). The results from biodistribution studies showed that all the three radiotracers have high tumor uptake and excellent tumor-to-background (T/B) ratios up to 4-h postinjection. After that time point, both 111In(DTPA-3P-RGD2) and 111In(DTPA-Bn-3P-RGD2) showed a much faster tumor washout and poorer T/B ratios than 111In(DOTA-3P-RGD2). The tumor uptake of 111In(DOTA-3P-RGD2) is integrin αvβ3- and RGD-specific. 111In(DOTA-3P-RGD2) is metabolically stable while only ~25% of 111In(DTPA-Bn-3P-RGD2) remains intact in the feces during 2-h period. On the basis of results from this study, it was concluded that 111In(DTPA-3P-RGD2) can be an effective integrin αvβ3-targeted radiotracer if the high-specific activity is required. However, DOTA remains to be the BFC of choice for the development of therapeutic lanthanide radiotracers.

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