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99mTcO(MAG2-3G3-dimer): a new integrin αvβ3-targeted SPECT radiotracer with high tumor uptake and favorable pharmacokinetics

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European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

This report presents the synthesis of a cyclic RGD dimer conjugate, MAG2-G3-E[G3-c(RGDfK)]2 (MAG2-3G3-dimer, G3 = Gly-Gly-Gly, MAG2 = S-benzoyl mercaptoacetylglycylglycyl), and evaluation of its 99mTc complex, 99mTcO(MAG2-3G3-dimer), as a new radiotracer for imaging the tumor integrin αvβ3 expression.

Methods

An in vitro displacement assay was used to determine the integrin αvβ3 binding affinity of MAG2-3G3-dimer against 125I-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) MAG2 is such a highly effective bifunctional chelator that 99mTcO(MAG2-3G3-dimer) can be prepared in high yield (radiochemical purity >95%) and with high specific activity (∼5 Ci/μmol) using a kit formulation; (2) 99mTcO(MAG2-3G3-dimer) has very high solution stability in the kit matrix; and (3) 99mTcO(MAG2-3G3-dimer) has very fast clearance kinetics from the intestine, liver, and kidneys. Among the 99mTc-labeled cyclic RGD peptides evaluated in the xenografted U87MG glioma models, 99mTcO(MAG2-3G3-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 99mTcO(MAG2-3G3-dimer) can be visualized with excellent contrast as early as 15 min postinjection. 99mTcO(MAG2-3G3-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

99mTcO(MAG2-3G3-dimer) is a very attractive radiotracer for early detection of integrin αvβ3-positive tumors and has significant advantages over the 18F-labeled RGD peptide radiotracers with respect to the cost, availability, and easiness for routine clinical preparation.

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Acknowledgment

This work is supported, in part, by Purdue University and research grants: R01 CA115883 A2 (S.L.) from National Cancer Institute (NCI), R21 HL083961-01 from National Heart, Lung, and Blood Institute (NHLBI), and DE-FG02-08ER64684 from the Department of Energy.

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Authors and Affiliations

  1. School of Health Sciences, Purdue University, 550 Stadium Mall Drive, West Lafayette, IN, 47907, USA

    Jiyun Shi, Lijun Wang, Young-Seung Kim, Shizhen Zhai & Shuang Liu

  2. Medical Isotopes Research Center, Peking University, Beijing, 100083, China

    Jiyun Shi, Bing Jia & Fan Wang

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  1. Jiyun Shi
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  2. Lijun Wang
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Correspondence to Shuang Liu.

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Shi, J., Wang, L., Kim, YS. et al. 99mTcO(MAG2-3G3-dimer): a new integrin αvβ3-targeted SPECT radiotracer with high tumor uptake and favorable pharmacokinetics. Eur J Nucl Med Mol Imaging 36, 1874–1884 (2009). https://doi.org/10.1007/s00259-009-1166-1

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