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Quantitative Analysis and Parametric Imaging of 18F-Labeled Monomeric and Dimeric RGD Peptides Using Compartment Model

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Abstract

Purpose

Non-invasive PET imaging with radiolabeled RGD peptides for αvβ3 integrin targeting has become an important tool for tumor diagnosis and treatment monitoring in both pre-clinical and clinical studies. To better understand the molecular process and tracer pharmacokinetics, we introduced kinetic modeling in the investigation of 18F-labeled RGD peptide monomer 18F-FP-c(RGDyK) (denoted as 18F-FPRGD) and dimer 18F-FP-PEG3-E[c(RGDyK)]2 (denoted as 18F-FPPRGD2).

Procedures

MDA-MB-435 tumor-bearing mice underwent 60 min dynamic PET scans following the injection of either 18F-FPRGD or 18F-FPPRGD2. Blocking studies with pre-injection of a blocking mass dose were performed for both monomeric and dimeric RGD groups. 18F-FPRAD (RAD) was used as a negative control. Kinetic parameters (K 1, k 2, k 3, k 4) of a three-compartment model were fitted to the dynamic data to allow quantitative comparisons between the monomeric and dimeric RGD peptides.

Results

Dimeric RGD peptide tracer showed significantly higher binding potential (BpND = k3/k4, 5.87 ± 0.31) than that of the monomeric analog (2.75 ± 0.48, p = 0.0022, n = 4/group). The BpND values showed a significantly greater ratio (dimer/monomer ~2.1) than the difference in %ID/g uptake measured from static images (dimer/monomer ~1.5, p = 0.0045). Significant decrease in BpND was found in the blocked groups compared with the unblocked ones (dimer p = 0.00024, monomer p = 0.005, n = 4/group). Similarly, the RAD control group showed the lowest BpND value among all the test groups, as the RAD peptide does not bind to integrin αvβ3. Volume of distribution (V T = K 1/k 2(1 + k 3/k 4)) could be separated into non-specific (V ND = K 1/k 2) and specific (V S = K 1 k 3/(k 2 k 4)) components. Specific distribution volume (V S) was the dominant component of V T in the unblocked groups and decreased in the blocked groups. Unblocked RGD dimer also showed higher V S than that of the monomer (dimer V S = 2.38 ± 0.15, monomer V S = 0.90 ± 0.17, p = 0.0013, n = 4/group), well correlated with BpND calculations. Little difference in V ND was found among all groups. Moreover, parametric maps allowed quantitative analysis at voxel level and provided higher tumor-to-background contrast for BpND maps than the static images. Tumor heterogeneity in kinetic parameters was found in parametric images, which could not be clearly identified in static intensity images.

Conclusions

The pharmacokinetics of both monomeric and dimeric RGD peptide tracers was compared, and the RGD dimers showed significantly higher binding affinity than the monomeric analogs. Kinetic parameters were demonstrated to be valuable for separating specific and non-specific binding and may allow more sensitive and detailed quantification than simple standardized uptake value analysis.

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Acknowledgments

This work was supported in part, by the Intramural Research Program of the National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH), the International Cooperative Program of the National Science Foundation of China (NSFC) (81028009), and NSFC Grants (60972099, 61027006). NG was partially sponsored by the China Scholarship Council (CSC).

Conflict of Interest Disclosure

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Biomedical Engineering, Huazhong University of Science and Technology, 505 Bldg. D11, 1037 Luoyu Rd., Wuhan, Hubei, China, 430074

    Ning Guo & Qingguo Xie

  2. Wuhan National Laboratory for Optoelectronics, Wuhan, Hubei, China

    Ning Guo & Qingguo Xie

  3. Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, 31 Center Dr., 1C22, Bethesda, MD, 20892, USA

    Ning Guo, Lixin Lang, Haokao Gao, Gang Niu, Dale O. Kiesewetter & Xiaoyuan Chen

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  1. Ning Guo
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  2. Lixin Lang
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  3. Haokao Gao
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  4. Gang Niu
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Correspondence to Qingguo Xie or Xiaoyuan Chen.

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Guo, N., Lang, L., Gao, H. et al. Quantitative Analysis and Parametric Imaging of 18F-Labeled Monomeric and Dimeric RGD Peptides Using Compartment Model. Mol Imaging Biol 14, 743–752 (2012). https://doi.org/10.1007/s11307-012-0541-7

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