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Biodistribution of the 18F-FPPRGD2 PET radiopharmaceutical in cancer patients: an atlas of SUV measurements

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

Abstract

Purpose

The aim of this study was to investigate the biodistribution of 2-fluoropropionyl-labeled PEGylated dimeric arginine-glycine-aspartic acid (RGD) peptide (PEG3-E[c{RGDyk}]2) (18F-FPPRGD2) in cancer patients and to compare its uptake in malignant lesions with 18F-FDG uptake.

Methods

A total of 35 patients (11 men, 24 women, mean age 52.1 ± 10.8 years) were enrolled prospectively and had 18F-FPPRGD2 PET/CT prior to treatment. Maximum standardized uptake values (SUVmax) and mean SUV (SUVmean) were measured in 23 normal tissues in each patient, as well as in known or suspected cancer lesions. Differences between 18F-FPPRGD2 uptake and 18F-FDG uptake were also evaluated in 28 of the 35 patients.

Results

Areas of high 18F-FPPRGD2 accumulation (SUVmax range 8.9 – 94.4, SUVmean range 7.1 – 64.4) included the bladder and kidneys. Moderate uptake (SUVmax range 2.1 – 6.3, SUVmean range 1.1 – 4.5) was found in the choroid plexus, salivary glands, thyroid, liver, spleen, pancreas, small bowel and skeleton. Compared with 18F-FDG, 18F-FPPRGD2 showed higher tumor-to-background ratio in brain lesions (13.4 ± 8.5 vs. 1.1 ± 0.5, P < 0.001), but no significant difference in body lesions (3.2 ± 1.9 vs. 4.4 ± 4.2, P = 0.10). There was no significant correlation between the uptake values (SUVmax and SUVmean) for 18F FPPRGD2 and those for 18F-FDG.

Conclusion

The biodistribution of 18F-FPPRGD2 in cancer patients is similar to that of other RGD dimer peptides and it is suitable for clinical use. The lack of significant correlation between 18F-FPPRGD2 and 18F-FDG uptake confirms that the information provided by each PET tracer is different.

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References

  1. Folkman J. Role of angiogenesis in tumor growth and metastasis. Semin Oncol. 2002;29:15–8.

    Article  CAS  PubMed  Google Scholar 

  2. Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature. 2000;407:249–57.

    Article  CAS  PubMed  Google Scholar 

  3. Bergers G, Benjamin LE. Tumorigenesis and the angiogenic switch. Nat Rev Cancer. 2003;3:401–10.

    Article  CAS  PubMed  Google Scholar 

  4. Jimenez B, Volpert OV. Mechanistic insights on the inhibition of tumor angiogenesis. J Mol Med. 2001;78:663–72.

    Article  CAS  PubMed  Google Scholar 

  5. Siemann DW, Chaplin DJ, Horsman MR. Vascular-targeting therapies for treatment of malignant disease. Cancer. 2004;100:2491–9.

    Article  CAS  PubMed  Google Scholar 

  6. Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science. 2005;307:58–62.

    Article  CAS  PubMed  Google Scholar 

  7. Ebos JM, Kerbel RS. Antiangiogenic therapy: impact on invasion, disease progression, and metastasis. Nat Rev Clin Oncol. 2011;8:210–21.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Brooks PC, Clark RA, Cheresh DA. Requirement of vascular integrin alpha v beta 3 for angiogenesis. Science. 1994;264:569–71.

    Article  CAS  PubMed  Google Scholar 

  9. Max R, Gerritsen RR, Nooijen PT, Goodman SL, Sutter A, Keilholz U, et al. Immunohistochemical analysis of integrin alpha vbeta3 expression on tumor-associated vessels of human carcinomas. Int J Cancer. 1997;71:320–4.

    Article  CAS  PubMed  Google Scholar 

  10. Wu WB, Peng HC, Huang TF. Disintegrin causes proteolysis of beta-catenin and apoptosis of endothelial cells. Involvement of cell-cell and cell-ECM interactions in regulating cell viability. Exp Cell Res. 2003;286:115–27.

    Article  CAS  PubMed  Google Scholar 

  11. Okada Y, Copeland BR, Hamann GF, Koziol JA, Cheresh DA, Del Zoppo GJ. Integrin alphavbeta3 is expressed in selected microvessels after focal cerebral ischemia. Am J Pathol. 1996;149:37–44.

    PubMed Central  CAS  PubMed  Google Scholar 

  12. Eliceiri BP, Cheresh DA. Role of alpha v integrins during angiogenesis. Cancer J. 2000;6 Suppl 3:S245–9.

    PubMed  Google Scholar 

  13. Felding-Habermann B, O’Toole TE, Smith JW, Fransvea E, Ruggeri ZM, Ginsberg MH, et al. Integrin activation controls metastasis in human breast cancer. Proc Natl Acad Sci U S A. 2001;98:1853–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Brooks PC, Montgomery AM, Rosenfeld M, Reisfeld RA, Hu T, Klier G, et al. Integrin alpha v beta 3 antagonists promote tumor regression by inducing apoptosis of angiogenic blood vessels. Cell. 1994;79:1157–64.

    Article  CAS  PubMed  Google Scholar 

  15. Shannon KE, Keene JL, Settle SL, Duffin TD, Nickols MA, Westlin M, et al. Anti-metastatic properties of RGD-peptidomimetic agents S137 and S247. Clin Exp Metastasis. 2004;21:129–38.

    Article  CAS  PubMed  Google Scholar 

  16. Haubner R, Wester HJ. Radiolabeled tracers for imaging of tumor angiogenesis and evaluation of anti-angiogenic therapies. Curr Pharm Des. 2004;10:1439–55.

    Article  CAS  PubMed  Google Scholar 

  17. Cai W, Chen X. Multimodality molecular imaging of tumor angiogenesis. J Nucl Med. 2008;49 Suppl 2:113S–28S.

    Article  CAS  PubMed  Google Scholar 

  18. Chen X. Multimodality imaging of tumor integrin alphavbeta3 expression. Mini Rev Med Chem. 2006;6:227–37.

    Article  CAS  PubMed  Google Scholar 

  19. Beer AJ, Haubner R, Goebel M, Luderschmidt S, Spilker ME, Wester HJ, et al. Biodistribution and pharmacokinetics of the alphavbeta3-selective tracer 18F-galacto-RGD in cancer patients. J Nucl Med. 2005;46:1333–41.

    CAS  PubMed  Google Scholar 

  20. Beer AJ, Haubner R, Sarbia M, Goebel M, Luderschmidt S, Grosu AL, et al. Positron emission tomography using [18F]Galacto-RGD identifies the level of integrin alpha(v)beta3 expression in man. Clin Cancer Res. 2006;12:3942–9.

    Article  CAS  PubMed  Google Scholar 

  21. Beer AJ, Niemeyer M, Carlsen J, Sarbia M, Nährig J, Watzlowik P, et al. Patterns of alphavbeta3 expression in primary and metastatic human breast cancer as shown by 18F-Galacto-RGD PET. J Nucl Med. 2008;49:255–9.

    Article  PubMed  Google Scholar 

  22. Beer AJ, Lorenzen S, Metz S, Herrmann K, Watzlowik P, Wester HJ, et al. Comparison of integrin alphaVbeta3 expression and glucose metabolism in primary and metastatic lesions in cancer patients: a PET study using 18F-galacto-RGD and 18F-FDG. J Nucl Med. 2008;49:22–9.

    Article  PubMed  Google Scholar 

  23. Haubner R, Weber WA, Beer AJ, Vabuliene E, Reim D, Sarbia M, et al. Noninvasive visualization of the activated alphavbeta3 integrin in cancer patients by positron emission tomography and [18F]Galacto-RGD. PLoS Med. 2005;2:e70.

    Article  PubMed Central  PubMed  Google Scholar 

  24. McParland BJ, Miller MP, Spinks TJ, Kenny LM, Osman S, Khela MK, et al. The biodistribution and radiation dosimetry of the Arg-Gly-Asp peptide 18F-AH111585 in healthy volunteers. J Nucl Med. 2008;49:1664–7.

    Article  PubMed  Google Scholar 

  25. Kenny LM, Coombes RC, Oulie I, Contractor KB, Miller M, Spinks TJ, et al. Phase I trial of the positron-emitting Arg-Gly-Asp (RGD) peptide radioligand 18F-AH111585 in breast cancer patients. J Nucl Med. 2008;49:879–86.

    Article  PubMed  Google Scholar 

  26. Boturyn D, Coll JL, Garanger E, Favrot MC, Dumy P. Template assembled cyclopeptides as multimeric system for integrin targeting and endocytosis. J Am Chem Soc. 2004;126:5730–9.

    Article  CAS  PubMed  Google Scholar 

  27. Liu S, Liu Z, Chen K, Yan Y, Watzlowik P, Wester HJ, et al. 18F-labeled galacto and PEGylated RGD dimers for PET imaging of αvβ3 integrin expression. Mol Imaging Biol. 2010;12:530–8.

    Article  PubMed Central  PubMed  Google Scholar 

  28. Mittra ES, Goris ML, Iagaru AH, Kardan A, Burton L, Berganos R, et al. Pilot pharmacokinetic and dosimetric studies of (18)F-FPPRGD2: a PET radiopharmaceutical agent for imaging α(v)β(3) integrin levels. Radiology. 2011;260:182–91.

    Article  PubMed Central  PubMed  Google Scholar 

  29. Iagaru A, Mosci C, Shen B, Chin FT, Mittra E, Telli ML, et al. 18F-FPPRGD2 PET/CT: pilot phase evaluation of breast cancer patients. Radiology. 2014;273:549–59.

    Article  PubMed  Google Scholar 

  30. Iagaru A, Mosci C, Jamali M, Minamimoto R, Mittra E, Shen B, et al. 18F FPPRGD2 PET/CT evaluation of patients with suspected recurrence of glioblastoma multiforme (abstract no. 31). J Nucl Med. 2014;55 Suppl 1:31.

    Google Scholar 

  31. Chin FT, Shen B, Liu S, Berganos RA, Chang E, Mittra E, et al. First experience with clinical-grade ([18F]FPP(RGD2): an automated multi-step radiosynthesis for clinical PET studies. Mol Imaging Biol. 2012;14:88–95.

    Article  PubMed Central  PubMed  Google Scholar 

  32. Delbeke D, Coleman RE, Guiberteau MJ, Brown ML, Royal HD, Siegel BA, et al. Procedure guideline for tumor imaging with 18F-FDG PET/CT 1.0. J Nucl Med. 2006;47:885–95.

    PubMed  Google Scholar 

  33. Wu Z, Li ZB, Cai W, He L, Chin FT, Li F, et al. 18F-labeled mini-PEG spacered RGD dimer (18F-FPRGD2): synthesis and microPET imaging of alphavbeta3 integrin expression. Eur J Nucl Med Mol Imaging. 2007;34:1823–31.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Zhang X, Xiong Z, Wu Y, Cai W, Tseng JR, Gambhir SS, et al. Quantitative PET imaging of tumor integrin alphavbeta3 expression with 18F-FRGD2. J Nucl Med. 2006;47:113–21.

    PubMed Central  CAS  PubMed  Google Scholar 

  35. Li ZB, Chen K, Chen X. (68)Ga-labeled multimeric RGD peptides for microPET imaging of integrin alpha(v)beta (3) expression. Eur J Nucl Med Mol Imaging. 2008;35:1100–8.

    Article  CAS  PubMed  Google Scholar 

  36. Li ZB, Cai W, Cao Q, Chen K, Wu Z, He L, et al. (64)Cu-labeled tetrameric and octameric RGD peptides for small-animal PET of tumor alpha(v)beta(3) integrin expression. J Nucl Med. 2007;48:1162–71.

    Article  CAS  PubMed  Google Scholar 

  37. Guo N, Lang L, Gao H, Niu G, Kiesewetter DO, Xie Q, et al. Quantitative analysis and parametric imaging of 18F-labeled monomeric and dimeric RGD peptides using compartment model. Mol Imaging Biol. 2012;14:743–52.

    Article  PubMed Central  PubMed  Google Scholar 

  38. Paulus W, Baur I, Schuppan D, Roggendorf W. Characterization of integrin receptors in normal and neoplastic human brain. Am J Pathol. 1993;143:154–63.

    PubMed Central  CAS  PubMed  Google Scholar 

  39. Singh B, Fu C, Bhattacharya J. Vascular expression of the alpha(v)beta(3)-integrin in lung and other organs. Am J Physiol Lung Cell Mol Physiol. 2000;278:L217–26.

    CAS  PubMed  Google Scholar 

  40. Terracio L, Rubin K, Gullberg D, Balog E, Carver W, Jyring R, et al. Expression of collagen binding integrins during cardiac development and hypertrophy. Circ Res. 1991;68:734–44.

    Article  CAS  PubMed  Google Scholar 

  41. Maitra N, Flink IL, Bahl JJ, Morkin E. Expression of a and b integrins during terminal differentiation of cardiomyocytes. Cardiovasc Res. 2000;47:715–25.

    Article  CAS  PubMed  Google Scholar 

  42. Hughes DE, Salter DM, Dedhar S, Simpson R. Integrin expression in human bone. J Bone Miner Res. 1993;8:527–33.

    Article  CAS  PubMed  Google Scholar 

  43. Annikki Liakka K. The integrin subunits α2, α3, α4, α5, α6, αV, β1 and β3 in fetal, infant and adult human spleen as detected by immunohistochemistry. Differentiation. 1994;56:183–90.

    Article  Google Scholar 

  44. Haubner R, Wester HJ, Burkhart F, Senekowitsch-Schmidtke R, Weber W, Goodman SL, et al. Glycosylated RGD-containing peptides: tracer for tumor targeting and angiogenesis imaging with improved biokinetics. J Nucl Med. 2001;42:326–36.

    CAS  PubMed  Google Scholar 

  45. Kim JH, Lee JS, Kang KW, Lee HY, Han SW, Kim TY, et al. Whole-body distribution and radiation dosimetry of (68)Ga-NOTA-RGD, a positron emission tomography agent for angiogenesis imaging. Cancer Biother Radiopharm. 2012;27:65–71.

    Article  CAS  PubMed  Google Scholar 

  46. Doss M, Kolb HC, Zhang JJ, Bélanger MJ, Stubbs JB, Stabin MG, et al. Biodistribution and radiation dosimetry of the integrin marker 18F-RGD-K5 determined from whole-body PET/CT in monkeys and humans. J Nucl Med. 2012;53:787–95.

    Article  PubMed  Google Scholar 

  47. Cirulli V, Beattie GM, Klier G, Ellisman M, Ricordi C, Quaranta V, et al. Expression and function of alpha(v)beta(3) and alpha(v)beta(5) integrins in the developing pancreas: roles in the adhesion and migration of putative endocrine progenitor cells. J Cell Biol. 2000;150:1445–60.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  48. Liu Z, Liu S, Wang F, Liu S, Chen X. Noninvasive imaging of tumor integrin expression using (18)F-labeled RGD dimer peptide with PEG (4) linkers. Eur J Nucl Med Mol Imaging. 2009;36:1296–307.

    Article  CAS  PubMed  Google Scholar 

  49. Giatromanolaki A, Koukourakis MI, Theodossiou D, et al. Comparative evaluation of angiogenesis assessment with anti-factor-VIII and anti-CD31 immunostaining in non-small cell lung cancer. Clin Cancer Res. 1997;3:2485–92.

    CAS  PubMed  Google Scholar 

  50. Lorger M, Krueger JS, O’Neal M, et al. Activation of tumor cell integrin alphavbeta3 controls angiogenesis and metastatic growth in the brain. Proc Natl Acad Sci U S A. 2009;106:10666–71.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  51. Morrison MS, Ricketts SA, Barnett J, Cuthbertson A, Tessier J, Wedge SR. Use of a novel Arg-Gly-Asp radioligand, 18F-AH111585, to determine changes in tumor vascularity after antitumor therapy. J Nucl Med. 2009;50:116–22.

    Article  CAS  PubMed  Google Scholar 

  52. Dumont RA, Hildebrandt I, Su H, et al. Noninvasive imaging of {alpha}V{beta}3 function as a predictor of the antimigratory and antiproliferative effects of dasatinib. Cancer Res. 2009;69:3173–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  53. Sun X, Yan Y, Liu S, et al. 18F-FPPRGD2 and 18F-FDG PET of response to Abraxane therapy. J Nucl Med. 2011;52:140–6.

    Article  PubMed  Google Scholar 

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Acknowledgments

We thank our research coordinators, the radiochemistry staff, and the nuclear medicine technologists. Special thank you to all the patients who agreed to participate in the study and their families.

Compliance with ethical standards

ᅟ

Funding

This study was partially funded by the Ben and Catherine Ivy Foundation and the Stanford Cancer Institute.

Conflicts of interest

S.S.G. Activities related to the present article: none to disclose. Activities not related to the present article: is on the board of Endra, Enlight, ImaginAB, MagArray, SiteOne Therapeutics, VisualSonics/Sonosite, and Click Diagnostics; is a consultant for VisualSonics/Sonosite, Gamma Medica, BMEB, and Bracco; received grants from General Electric and Sanofi-Aventis; received honoraria from ImaginAB; holds stock in Enlight and VisualSonics/Sonosite; received compensation for travel and accommodation from Gamma Camera.

A.I. Activities related to the present article: none to disclose. Activities not related to the present article: received grants from GE Healthcare and Bayer Healthcare.

R.M., M.J., A.B..., C.M., E.M., B.S., and F.T.C. declare no conflicts of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the principles of the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Research support

Ben and Catherine Ivy Foundation; Stanford Cancer Institute.

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Authors and Affiliations

  1. Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Stanford University, Stanford, CA 300 Pasteur Drive, C21, Stanford, CA, 94305-5281, USA

    Ryogo Minamimoto, Mehran Jamali, Amir Barkhodari, Camila Mosci, Erik Mittra, Sanjiv Sam Gambhir & Andrei Iagaru

  2. Molecular Imaging Program at Stanford (MIPS), Department of Radiology, Stanford University, Stanford, CA, USA

    Ryogo Minamimoto, Mehran Jamali, Bin Shen, Frederick Chin & Sanjiv Sam Gambhir

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  1. Ryogo Minamimoto
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  2. Mehran Jamali
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  3. Amir Barkhodari
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  4. Camila Mosci
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  5. Erik Mittra
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  6. Bin Shen
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  7. Frederick Chin
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  8. Sanjiv Sam Gambhir
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  9. Andrei Iagaru
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Correspondence to Andrei Iagaru.

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Minamimoto, R., Jamali, M., Barkhodari, A. et al. Biodistribution of the 18F-FPPRGD2 PET radiopharmaceutical in cancer patients: an atlas of SUV measurements. Eur J Nucl Med Mol Imaging 42, 1850–1858 (2015). https://doi.org/10.1007/s00259-015-3096-4

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  • DOI: https://doi.org/10.1007/s00259-015-3096-4

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