99mTc-Labeled cyclic RGD dimers with high tumor uptake and favorable pharmacokinetics for imaging tumor integrin avb3 expression

Objectives The objective is to explore the impact of bifunctional chelators on integrin α_vβ₃ binding affinity of cyclic RGD dimers and the ^99mTc chelates on radiotracer tumor uptake and excretion kinetics.

Methods MAG₂-PEG₄-E[PEG₄-c(RGDfK)]₂ (3PEG₄-dimer) and MAG₂-G₃-E[G₃-c(RGDfK)]₂ (3G₃-dimer) were prepared. An in vitro competitive displacement assay was used to determine their α_vβ₃ binding affinity. ^99mTc labeled compounds were evaluated for imaging integrin α_vβ₃ in xenografted U87MG glioma.

Results MAG₂-3PEG₄-dimer and MAG₂-3G₃-dimer are bivalent in binding to integrin α_vβ₃. Replacing [^99mTc(HYNIC)(tricine)(TPPTS)] with a smaller ^99mTcO(MAG₂) resulted in higher tumor uptake. ^99mTcO(MAG₂-3PEG₄-dimer) has high tumor uptake (16.78±5.46 %ID/g at 30 min p.i. and 13.60±2.30 %ID/g at 120 min p.i.) and ^99mTcO(MAG₂-3G₃-dimer) has the best T/B ratios (tumor/liver=4.29±1.00 at 30 min p.i. and 8.29±1.50 at 120 min p.i.; tumor/kidney=1.16±0.19 at 30 min p.i. and 2.49±0.25 at 120 min p.i.). The tumors can be visualized with excellent contrast as early as 15 min p.i. using ^99mTcO(MAG₂-3G₃-dimer).

Conclusions ^99mTcO(MAG₂-3PEG₄-dimer) and ^99mTcO(MAG₂-3G₃-dimer) are very attractive radiotracers for early detection of integrin α_vβ₃–positive tumors and non-invasive monitoring of tumor growth. ^99mTcO(MAG₂-3PEG₄-dimer) and ^99mTcO(MAG₂-3G₃-dimer) have significant advantages ¹⁸F-labeled cyclic RGD peptide radiotracers with respect to the cost, availability and easiness of routine clinical preparation.