99mTcO(MAG2-3G3-dimer): a new integrin alpha(v)beta(3)-targeted SPECT radiotracer with high tumor uptake and favorable pharmacokinetics.

Abstract

PURPOSE:

This report presents the synthesis of a cyclic RGD dimer conjugate, MAG(2)-G(3)-E[G(3)-c(RGDfK)](2) (MAG(2)-3G(3)-dimer, G(3) = Gly-Gly-Gly, MAG(2) = S-benzoyl mercaptoacetylglycylglycyl), and evaluation of its (99m)Tc complex, (99m)TcO(MAG(2)-3G(3)-dimer), as a new radiotracer for imaging the tumor integrin alpha(v)beta(3) expression.

METHODS:

An in vitro displacement assay was used to determine the integrin alpha(v)beta(3) binding affinity of MAG(2)-3G(3)-dimer against (125)I-c(RGDyK) bound to U87MG human glioma cells. The athymic nude mice bearing U87MG glioma xenografts were used for biodistribution and planar imaging studies.

RESULTS:

We found that (1) MAG(2) is such a highly effective bifunctional chelator that (99m)TcO(MAG(2)-3G(3)-dimer) can be prepared in high yield (radiochemical purity >95%) and with high specific activity ( approximately 5 Ci/micromol) using a kit formulation; (2) (99m)TcO(MAG(2)-3G(3)-dimer) has very high solution stability in the kit matrix; and (3) (99m)TcO(MAG(2)-3G(3)-dimer) has very fast clearance kinetics from the intestine, liver, and kidneys. Among the (99m)Tc-labeled cyclic RGD peptides evaluated in the xenografted U87MG glioma models, (99m)TcO(MAG(2)-3G(3)-dimer) has the best pharmacokinetics and tumor to background ratios (tumor/liver = 4.29 +/- 1.00 at 30 min postinjection and 8.29 +/- 1.50 at 120 min postinjection; tumor/kidney = 1.16 +/- 0.19 at 30 min postinjection and 2.49 +/- 0.25 at 120 min postinjection). Planar imaging studies showed that tumors in the glioma-bearing mice administered with (99m)TcO(MAG(2)-3G(3)-dimer) can be visualized with excellent contrast as early as 15 min postinjection. (99m)TcO(MAG(2)-3G(3)-dimer) was able to maintain its chemical integrity in kidneys (>80% intact) and liver (>95% intact) over the 2-h period. However, there was significant metabolism (>50% of the injected radioactivity) detected in both urine and feces samples.

CONCLUSION:

(99m)TcO(MAG(2)-3G(3)-dimer) is a very attractive radiotracer for early detection of integrin alpha(v)beta(3)-positive tumors and has significant advantages over the (18)F-labeled RGD peptide radiotracers with respect to the cost, availability, and easiness for routine clinical preparation.

• Authors: Jiyun Shi, Lijun Wang, Young-Seung Kim, Shizhen Zhai, Bing Jia, Fan Wang, Shuang Liu
• Journal: European journal of nuclear medicine and molecular imaging (Eur J Nucl Med Mol Imaging) Vol. 36 Issue 11 Pg. 1874-84 (Nov 2009) ISSN: 1619-7089 [Electronic] Germany
• PMID: 19484236 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• 99mTcO(MAG2-3G3-dimer)
• Chelating Agents
• Integrin alphaVbeta3
• Oligopeptides
• Organotechnetium Compounds
• Radioactive Tracers
• arginyl-glycyl-aspartic acid

Topics

• Animals
• Cell Line, Tumor
• Chelating Agents (chemistry)
• Female
• Humans
• Integrin alphaVbeta3 (metabolism)
• Mice
• Neoplasms (diagnostic imaging, metabolism, pathology)
• Oligopeptides (chemistry, pharmacology)
• Organotechnetium Compounds (chemistry, metabolism, pharmacokinetics)
• Radioactive Tracers
• Radiochemistry
• Substrate Specificity
• Tissue Distribution (drug effects)
• Tomography, Emission-Computed, Single-Photon
• Tumor Burden