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Preclinical evaluation of novel organometallic 99mTc-folate and 99mTc-pteroate radiotracers for folate receptor-positive tumour targeting

  • Molecular imaging
  • Published:
European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

The folate receptor (FR) is a valuable tumour marker, since it is frequently overexpressed on various cancer types. The purpose of the present study was to pre-clinically evaluate novel site-specifically modified 99mTc(CO)3 folate (γ-derivative 4, α-derivative 5) and pteroate (6) conjugates for FR targeting.

Methods

The 99mTc(CO)3 radiotracers 4–6 were prepared by a kit-like procedure. In vitro characterisation (K D and B max) of the radiotracers was performed with FR-positive KB cells. Tissue distribution was studied in tumour-bearing mice. SPECT/CT experiments were performed with a dedicated small animal SPECT/CT scanner.

Results

The complexes 4–6 were formed in high yields (>92%). Binding constants of the radiotracers (K D in nM: 4: 2.09; 5: 2.51; 6: 14.52) were similar to those of 3H-folic acid (K D in nM: 7.22). In vivo the folate derivatives showed significantly better tumour uptake (4: 2.3±0.4% ID/g and 5: 1.2±0.2% ID/g, 4 h p.i.) than the pteroate derivative (6: 0.4±0.2% ID/g, 4 h p.i.). Clearance of all radiotracers from the blood pool and from non-targeted tissues was efficient (tumour to blood ratio approx. 200–350, 24 h p.i.). FR-positive tissue and organs were successfully visualised via small animal SPECT/CT.

Conclusion

Radiotracers 4–6 are the first 99mTc(CO)3 tracers prepared via a kit formulation which exhibit full biological activity in vitro and in vivo. Folate derivatives 4 and 5 revealed significantly better pharmacokinetic properties than the pteroate derivative 6. Promising pre-clinical SPECT results warrant further assessment of 99mTc(CO)3 radiofolates for detection of FR-positive tumours.

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Acknowledgements

We thank Dr. Ilse Novak-Hofer, Dr. Robert Waibel and Dr. Elisa Garcia-Garayoa for valuable discussions and Alain Blanc, Judith Stahel and Christine De Pasquale for technical assistance. This work was financially supported by Mallinckrodt-Tyco Inc. and Merck Eprova AG.

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Authors and Affiliations

  1. Center for Radiopharmaceutical Science ETH-PSI-USZ, Paul Scherrer Institute, 5232, Villigen-PSI, Switzerland

    Cristina Müller, Alexander Hohn, P. August Schubiger & Roger Schibli

  2. Department of Chemistry and Applied Biosciences of the ETH, Institute for Pharmaceutical Sciences, ETH Hönggerberg, HCI H425, Wolfgang-Pauli-Strasse 10, 8093, Zürich, Switzerland

    P. August Schubiger & Roger Schibli

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  1. Cristina Müller
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Correspondence to Roger Schibli.

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Müller, C., Hohn, A., Schubiger, P.A. et al. Preclinical evaluation of novel organometallic 99mTc-folate and 99mTc-pteroate radiotracers for folate receptor-positive tumour targeting. Eur J Nucl Med Mol Imaging 33, 1007–1016 (2006). https://doi.org/10.1007/s00259-006-0111-9

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  • DOI: https://doi.org/10.1007/s00259-006-0111-9

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