A Novel 68Ga-Labeled Pteroic Acid-Based PET Tracer for Tumor Imaging via the Folate Receptor

  • Berit Kühle
  • Cristina Müller
  • Tobias L. Ross
Conference paper
Part of the Recent Results in Cancer Research book series (RECENTCANCER, volume 194)


The folate receptor (FR) is a very attractive target in oncological imaging as it is overexpressed by a variety of cancer types, whereas the expression in healthy tissue is very limited. The synthesis of regioisomeric pure folic acid derivatives normally requires a regioselective approach and does not allow the use of native folic acid (FA). As the pharmacophore of FA is assumed to be pteroic acid, its use without the glutamic acid moiety may enable the possibility to considerably simplify the synthesis of a positron emission tomography (PET) tracer for FR imaging. In this work, DO3A-EA-Pte was successfully synthesized and labeled with 68Ga. It is stable for up to 3 h in PBS and against transchelation by transferrin. It also displays a lipophilicity that allows the assumption that it will show favorable in vivo characteristics for FR imaging via PET.


Positron Emission Tomography Folic Acid Radiochemical Yield Folate Receptor Reduce Folate Carrier 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



We gratefully thank Merck and Cie, Schaffhausen, Switzerland for providing us with the protected pteroic acid.


  1. Antony AC (1992) The biological chemistry of folate receptors. Blood 79:2807–2820PubMedGoogle Scholar
  2. Duimstra JA, Femia FJ, Meade TJ (2005) A gadolinium chelate for detection of β-glucuronidase: a self-immolative approach. J Am Chem Soc 127:12847–12855PubMedCrossRefGoogle Scholar
  3. Guo H, Xie F, Zhu M et al (2011) The synthesis of pteroyl-lys conjugates and its application as technetium-99m labeled radiotracer for folate receptor-positive tumor targeting. Bioorg Med Chem Lett 21:2025–2029PubMedCrossRefGoogle Scholar
  4. Kamen BA, Capdevila A (1986) Receptor-mediated folate accumulation is regulated by the cellular folate content. Proc Natl Acad Sci USA 83:5983–5987PubMedCrossRefGoogle Scholar
  5. Ke C-Y, Mathias CJ, Green MA (2005) Targeting the tumor-associated folate receptor with an 111In−DTPA conjugate of pteroic acid. J Am Chem Soc 127:7421–7426PubMedCrossRefGoogle Scholar
  6. Leamon CP, Low PS (2001) Folate-mediated targeting: from diagnostics to drug and gene delivery. Drug Discov Today 6:44–51PubMedCrossRefGoogle Scholar
  7. Leamon CP, Parker MA, Vlahov IR et al (2002) Synthesis and biological evaluation of EC20: a new folate-derived, 99mTc-based radiopharmaceutical. Bioconjugate Chem 13:1200–1210CrossRefGoogle Scholar
  8. Leamon C, You F, Santhapuram H et al (2009) Properties influencing the relative binding affinity of pteroate derivatives and drug conjugates thereof to the folate receptor. Pharm Res 26:1315–1323PubMedCrossRefGoogle Scholar
  9. Mathias CJ, Wang S, Waters DJ et al (1998) Indium-111-DTPA-folate as a potential folate receptor-targeted radiopharmaceutical. J Nucl Med 39:1579–1585PubMedGoogle Scholar
  10. Müller C, Dumas C, Hoffmann U et al (2004) Organometallic 99mTc-technetium(I)- and Re-rhenium(I)-folate derivatives for potential use in nuclear medicine. J Organomet Chem 689:4712–4721CrossRefGoogle Scholar
  11. Ross JF, Chaudhuri PK, Ratnam M (1994) Differential regulation of folate receptor isoforms in normal and malignant tissues in vivo and in established cell lines. Physiologic and clinical implications. Cancer 73:2432–2443Google Scholar
  12. Ross TL, Honer M, Lam PYH et al (2008) Fluorine-18 click radiosynthesis and preclinical evaluation of a new 18F-labeled folic acid derivative. Bioconjugate Chem 19:2462–2470CrossRefGoogle Scholar
  13. Toffoli G, Cernigoi C, Russo A et al (1997) Overexpression of folate binding protein in ovarian cancers. Int J Cancer 74:193–198PubMedCrossRefGoogle Scholar
  14. Weitman SD, Weinberg AG, Coney LR et al (1992) Cellular localization of the folate receptor: potential role in drug toxicity and folate homeostasis. Cancer Res 52:6708–6711PubMedGoogle Scholar
  15. Zhernosekov KP, Filosofov DV, Baum RP et al (2007) Processing of generator-produced 68Ga for medical application. J Nucl Med 48:1741–1748 PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Berit Kühle
    • 1
  • Cristina Müller
    • 2
  • Tobias L. Ross
    • 1
  1. 1.Johannes Gutenberg-UniversityMainzGermany
  2. 2.Center for Radiopharmaceutical Sciences of ETH, PSI and USZPaul Scherrer InstituteVilligen-PSISwitzerland

Personalised recommendations