The RGD (arginine, glycine, aspartic acid) sequence is known to be an important binding motif for various integrins that are over-expressed in many tumor types. Magnetic resonance molecular imaging of integrin receptors is in general hampered by the inherently low sensitivity of MRI. Here, we report a novel design of integrin targeting MRI agents in which the 1,4,7,10-tetraazacyclododecane macrocycle is integrated into the rigid cyclic peptide framework through the 1 and 7 acetate sidearms of the DOTA unit [c(DOTA-RGDf) and c(DOTA-RGD), DOTA = the 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, f = D-Phenylalanine]. The rationale of this design is that binding of these Gd-complexes to integrin would result in an slower tumbling rate, which in turn would increase T1 relaxivity as predicted by the Solomon Bloembergen Morgan theory. The chelating properties of c(DOTA-RGD) and c(DOTA-RGDf) with Yb3+, Gd3+, and Cu2+ were studied in solution. High resolution 1H NMR studies revealed that the Yb3+complex adopted a SAP geometry. UV-Vis spectroscopy showed that Cu2+complex had a distorted octahedral geometry. We have shown that the Lu3+ complex of c(DOTA-RGD) binds to avb3 integrin with an IC50 values of 5.2. PET imaging experiments with the 64Cu2+c(RGDf-DOTA) complex in U87MG tumor bearing mice confirmed that the metal complex localizes to tumor. The relaxivity of the Gd3+ complex was found to be 3.1, in agreement with the reported relaxivity of the Gd-complexes of other DOTA-bisamide ligands. The water exchange properties of these two complexes in the presence and absence of integrin and the integrin binding properties of these two topological complexes will be studied.

Conformationally restricted integrin targeting imaging agents

247th National Meeting (2014)

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