Cell adhesion molecules alphavbeta3 and alphavbeta5 play a pivotal role in
tumor angiogenesis and
metastasis. Antiangiogenic
therapy by using small
peptide antagonists of alphav-
integrins slows
tumor growth and prevents
tumor spread. The ability to visualize and quantify
integrin expression will enable selection of appropriate patients for clinical trials, following determination of treatment efficacy and development of new potent drugs. We have previously labeled
cyclic RGD peptide c(RGDyK) with 125I and 18F and applied the radiotracers to both subcutaneous and orthotopic
brain tumor models. Here we conjugated c(RGDyK) with 1,4,7,10-tetraaza-1,4,7,10-tetradodecane-N,N',N' ',N' "-tetraacetic
acid (
DOTA) and labeled the
DOTA-RGD conjugate with 64Cu (t1/2) = 12.8 h, 19% beta+) in high radiochemical purity and specific activity. The
tumor targeting ability and in vivo kinetics of 64Cu-
DOTA-RGD was compared with [18F]FB-RGD and 125I-RGD in orthotopic MDA-MB-435
breast cancer model. All three radiotracers revealed fast blood clearance and high
tumor-to-blood and
tumor-to-muscle ratios. 125I-RGD had higher
tumor uptake than the corresponding 18F and 64Cu analogues. [18F]FB-RGD indicated a fast
tumor washout rate and an unfavorable hepatobiliary excretion pathway, resulting in significant activity accumulation in gallbladder and intestines. 64Cu-
DOTA-RGD had prolonged
tumor retention (1.44 +/- 0.09 %ID/g at 4 h postinjection) and persistent uptake in the liver. All three tracers revealed receptor specific
tumor accumulation which were illustrated by effective blocking via coinjection with a blocking dose of c(RGDyK). Static microPET imaging and whole-body autoradiography showed strong contrast from the contralateral background. In conclusion, overall molecular charge and characteristics of radiolabels have profound effects on
tumor accumulation and in vivo kinetics of radiolabeled
RGD peptide. Further modification of the
RGD peptide and optimization of the tracer for prolonged
tumor uptake and improved in vivo kinetics are being explored.