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Biodistribution and Radiation Dosimetry of the Carbonic Anhydrase IX Imaging Agent [18 F]VM4-037 Determined from PET/CT Scans in Healthy Volunteers

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Abstract

Purpose

[18 F]VM4-037 has been developed as a positron emission tomography (PET) imaging marker to detect carbonic anhydrase IX (CA-IX) overexpression and is being investigated for use as a surrogate marker for tissue hypoxia. The purpose of this study was to determine the biodistribution and estimate the radiation dose from [18 F]VM4-037 using whole-body PET/CT scans in healthy human volunteers.

Procedures

Successive whole-body PET/CT scans were performed after intravenous injection of [18 F]VM4-037 in four healthy humans. The radiotracer uptakes in different organs were determined from the analysis of the PET scans. Human radiation doses were estimated using OLINDA/EXM software.

Results

High uptake of [18 F]VM4-037 was observed in the liver and kidneys, with little clearance of activity during the study period, with mean standardized uptake values of ~35 in liver and ~22 in kidneys at ~1 h after injection. The estimated effective dose was 28 ± 1 μSv/MBq and the absorbed doses for the kidneys and liver were 273 ± 31 and 240 ± 68 μGy/MBq, respectively, for the adult male phantom. Hence, the effective dose would be 10 ± 0.5 mSv for the anticipated injected activity of 370 MBq, and the kidney and liver doses would be 101 ± 11 and 89 ± 25 mGy, respectively.

Conclusions

[18 F]VM4-037 displayed very high uptake in the liver and kidneys with little clearance of activity during the study period, resulting in these organs receiving the highest radiation doses among all bodily organs. Though the effective dose and the organ doses are within the limits considered as safe, the enhanced uptake of [18 F]VM4-037 in the kidneys and liver will make the compound unsuitable for imaging overexpression of CA-IX in those two organs. However, the tracer may be suitable for imaging overexpression of CA-IX in lesions in other regions of the body such as in the lungs or head and neck region.

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References

  1. Potter C, Harris AL (2004) Hypoxia inducible carbonic anhydrase IX, marker of tumour hypoxia, survival pathway and therapy target. Cell Cycle 3:164–167

    Article  PubMed  CAS  Google Scholar 

  2. Pastorek J, Pastorekova S (2004) Cancer-related carbonic anhydrase isozymes and their inhibition. CRC, Boca Raton

    Google Scholar 

  3. Ivanov S, Liao SY, Ivanova A et al (2001) Expression of hypoxia-inducible cell-surface transmembrane carbonic anhydrases in human cancer. Am J Pathol 158:905–919

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  4. Winum JY, Rami M, Scozzafava A et al (2008) Carbonic anhydrase IX: a new druggable target for the design of antitumor agents. Med Res Rev 28:445–463

    Article  PubMed  CAS  Google Scholar 

  5. Pastorekova S, Parkkila S, Zavada J (2006) Tumor-associated carbonic anhydrases and their clinical significance. Adv Clin Chem 42:167–216

    Article  PubMed  CAS  Google Scholar 

  6. Potter CP, Harris AL (2003) Diagnostic, prognostic and therapeutic implications of carbonic anhydrases in cancer. Br J Cancer 89:2–7

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  7. Wykoff CC, Beasley NJ, Watson PH et al (2000) Hypoxia-inducible expression of tumor-associated carbonic anhydrases. Cancer Res 60:7075–7083

    PubMed  CAS  Google Scholar 

  8. Chen L, Zhang Z, Kolb HC et al (2012) (1)(8)F-HX4 hypoxia imaging with PET/CT in head and neck cancer: a comparison with (1)(8)F-FMISO. Nucl Med Commun 33:1096–1102

    Article  PubMed  CAS  Google Scholar 

  9. Ilie M, Mazure NM, Hofman V et al (2010) High levels of carbonic anhydrase IX in tumour tissue and plasma are biomarkers of poor prognostic in patients with non-small cell lung cancer. Br J Cancer 102:1627–1635

    Article  PubMed  CAS  Google Scholar 

  10. Jarvela S, Parkkila S, Bragge H et al (2008) Carbonic anhydrase IX in oligodendroglial brain tumors. BMC Cancer 8:1

    Article  PubMed  PubMed Central  Google Scholar 

  11. Bui MH, Seligson D, Han KR et al (2003) Carbonic anhydrase IX is an independent predictor of survival in advanced renal clear cell carcinoma: implications for prognosis and therapy. Clin Cancer Res 9:802–811

    PubMed  CAS  Google Scholar 

  12. Chia SK, Wykoff CC, Watson PH et al (2001) Prognostic significance of a novel hypoxia-regulated marker, carbonic anhydrase IX, in invasive breast carcinoma. J Clin Oncol 19:3660–3668

    PubMed  CAS  Google Scholar 

  13. Loncaster JA, Harris AL, Davidson SE et al (2001) Carbonic anhydrase (CA IX) expression, a potential new intrinsic marker of hypoxia: correlations with tumor oxygen measurements and prognosis in locally advanced carcinoma of the cervix. Cancer Res 61:6394–6399

    PubMed  CAS  Google Scholar 

  14. Kaanders JH, Wijffels KI, Marres HA et al (2002) Pimonidazole binding and tumor vascularity predict for treatment outcome in head and neck cancer. Cancer Res 62:7066–7074

    PubMed  CAS  Google Scholar 

  15. Tanaka N, Kato H, Inose T et al (2008) Expression of carbonic anhydrase 9, a potential intrinsic marker of hypoxia, is associated with poor prognosis in oesophageal squamous cell carcinoma. Br J Cancer 99:1468–1475

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  16. Patard JJ, Fergelot P, Karakiewicz PI et al (2008) Low CAIX expression and absence of VHL gene mutation are associated with tumor aggressiveness and poor survival of clear cell renal cell carcinoma. Int J Cancer 123:395–400

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  17. McDonald PC, Winum JY, Supuran CT, Dedhar S (2012) Recent developments in targeting carbonic anhydrase IX for cancer therapeutics. Oncotarget 3:84–97

    PubMed  PubMed Central  Google Scholar 

  18. Divgi CR, Uzzo RG, Gatsonis C et al (2013) Positron emission tomography/computed tomography identification of clear cell renal cell carcinoma: results from the REDECT trial. J Clin Oncol 31:187–194

    Article  PubMed  Google Scholar 

  19. Neri D, Supuran CT (2011) Interfering with pH regulation in tumours as a therapeutic strategy. Nat Rev Drug Discov 10:767–777

    Article  PubMed  CAS  Google Scholar 

  20. Supuran CT (2008) Carbonic anhydrases: novel therapeutic applications for inhibitors and activators. Nat Rev Drug Discov 7:168–181

    Article  PubMed  CAS  Google Scholar 

  21. Kolb HC, Walsh JC, Dhanalakshmi K, et al. (2010) Development of molecular imaging probes for carbonic anhydrase-IX using click chemistry. US Patent US20100317842-A1. Issued Dec 16, 2010

  22. Stabin MG, Sparks RB, Crowe E (2005) OLINDA/EXM: the second-generation personal computer software for internal dose assessment in nuclear medicine. J Nucl Med 46:1023–1027

    PubMed  Google Scholar 

  23. Doss M, Kolb HC, Zhang JJ et al (2012) Biodistribution and radiation dosimetry of the integrin marker 18 F-RGD-K5 determined from whole-body PET/CT in monkeys and humans. J Nucl Med 53:787–795

    Article  PubMed  Google Scholar 

  24. FDA (2010) Guidance for industry and researchers. The Radioactive Drug Research Committee: Human Research Without an Investigational New Drug Application. FDA, Silver Spring, MD

    Google Scholar 

  25. Stabin M, Stubbs J, Toohey R (1996) Radiation dose estimates for radiopharmaceuticals, NUREG/CR-6345

  26. Hasannejad H, Takeda M, Taki K et al (2004) Interactions of human organic anion transporters with diuretics. J Pharmacol Exp Ther 308:1021–1029

    Article  PubMed  CAS  Google Scholar 

  27. Pastorekova S, Parkkila S, Pastorek J, Supuran CT (2004) Carbonic anhydrases: current state of the art, therapeutic applications and future prospects. J Enzym Inhib Med Chem 19:199–229

    Article  CAS  Google Scholar 

  28. Pastorekova S, Casini A, Scozzafava A et al (2004) Carbonic anhydrase inhibitors: the first selective, membrane-impermeant inhibitors targeting the tumor-associated isozyme IX. Bioorg Med Chem Lett 14:869–873

    Article  PubMed  CAS  Google Scholar 

  29. Emara M, Turner AR, Allalunis-Turner J (2010) Hypoxic regulation of cytoglobin and neuroglobin expression in human normal and tumor tissues. Cancer Cell Int 10:33

    Article  PubMed  PubMed Central  Google Scholar 

  30. Takacova M, Bartosova M, Skvarkova L et al (2013) Carbonic anhydrase IX is a clinically significant tissue and serum biomarker associated with renal cell carcinoma. Oncol Lett 5:191–197

    PubMed  CAS  PubMed Central  Google Scholar 

  31. Betof AS, Rabbani ZN, Hardee ME et al (2012) Carbonic anhydrase IX is a predictive marker of doxorubicin resistance in early-stage breast cancer independent of HER2 and TOP2A amplification. Br J Cancer 106:916–922

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  32. Kim SJ, Rabbani ZN, Dewhirst MW et al (2005) Expression of HIF-1alpha, CA IX, VEGF, and MMP-9 in surgically resected non-small cell lung cancer. Lung Cancer 49:325–335

    Article  PubMed  Google Scholar 

  33. Kim SJ, Rabbani ZN, Vollmer RT et al (2004) Carbonic anhydrase IX in early-stage non-small cell lung cancer. Clin Cancer Res 10:7925–7933

    Article  PubMed  CAS  Google Scholar 

  34. Li Y, Wang H, Oosterwijk E et al (2009) Expression and activity of carbonic anhydrase IX is associated with metabolic dysfunction in MDA-MB-231 breast cancer cells. Cancer Invest 27:613–623

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  35. Wolburg H, Noell S, Fallier-Becker P et al (2012) The disturbed blood–brain barrier in human glioblastoma. Mol Aspects Med 33:579–589

    Article  PubMed  CAS  Google Scholar 

  36. McDonald PC, Winum JY, Supuran CT, Dedhar S (2012) Recent developments in targeting carbonic anhydrase IX for cancer therapeutics. Oncotarget 3:84–97

    PubMed  PubMed Central  Google Scholar 

  37. Doss M, Zhang JJ, Belanger MJ et al (2010) Biodistribution and radiation dosimetry of the hypoxia marker 18 F-HX4 in monkeys and humans determined by using whole-body PET/CT. Nucl Med Commun 31:1016–1024

    PubMed  CAS  PubMed Central  Google Scholar 

  38. Haubner R, Kuhnast B, Mang C et al (2004) [18 F]Galacto-RGD: synthesis, radiolabeling, metabolic stability, and radiation dose estimates. Bioconjug Chem 15:61–69

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We wish to thank the nuclear medicine staff at the PET center including Donna Mosley for performing the PET/CT scans. We also wish to thank Mary Benetz and the staff from the Protocol Management Office for help with this research protocol. The help of the staff from Clinical Research Unit and Protocol Support Laboratory is gratefully acknowledged. The study was conducted at Fox Chase Cancer Center under a research contract with Siemens Molecular Imaging Inc. The study is registered in ClinicalTrials.gov with the identifier NCT00884520 and IND number 104438.

Conflict of Interest

Joseph C. Walsh and Zhihong Zhu are employees of Siemens Molecular Imaging Inc. Hartmuth C. Kolb, Vani P. Mocharla, and Michael Haka were previously employees of Siemens Molecular Imaging Inc. at the time of the work described here. Fox Chase Cancer Center performed the research work described in this paper under a research contract with Siemens Molecular Imaging Inc. None of the authors received any additional compensation for performing this work.

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Authors and Affiliations

  1. Diagnostic Imaging, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111-2497, USA

    Mohan Doss & Jian Q. Yu

  2. Biomarker Research, Siemens Molecular Imaging Inc., Culver City, CA, USA

    Hartmuth C. Kolb, Joseph C. Walsh & Vani P. Mocharla

  3. Biomarker Research, Siemens Molecular Imaging Inc., North Wales, PA, USA

    Zhihong Zhu & Michael Haka

  4. Protocol Lab, Fox Chase Cancer Center, Philadelphia, PA, USA

    R. Katherine Alpaugh

  5. Department of Surgery, Fox Chase Cancer Center, Philadelphia, PA, USA

    David Y. T. Chen

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  1. Mohan Doss
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  2. Hartmuth C. Kolb
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  4. Vani P. Mocharla
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  5. Zhihong Zhu
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  9. Jian Q. Yu
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Correspondence to Jian Q. Yu.

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Doss, M., Kolb, H.C., Walsh, J.C. et al. Biodistribution and Radiation Dosimetry of the Carbonic Anhydrase IX Imaging Agent [18 F]VM4-037 Determined from PET/CT Scans in Healthy Volunteers. Mol Imaging Biol 16, 739–746 (2014). https://doi.org/10.1007/s11307-014-0730-7

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