Radiolabeled bombesin analogs for prostate cancer diagnosis: preclinical studies

Faintuch, Bluma Linkowski; Teodoro, Rodrigo; Duatti, Adriano; Muramoto, Emiko; Faintuch, Salomao; Smith, Charles J.

doi:10.1016/j.nucmedbio.2008.02.005

« Previous Next »Nuclear Medicine and Biology
Volume 35, Issue 4 , Pages 401-411, May 2008

Radiolabeled bombesin analogs for prostate cancer diagnosis: preclinical studies

Bluma Linkowski Faintuch
- Radiopharmacy Center, Institute of Energetic and Nuclear Research, Sao Paulo, SP 05508-000, Brazil
- Corresponding author. Tel.: +55 11 38169252; fax: +55 11 38120253.
Rodrigo Teodoro
- Radiopharmacy Center, Institute of Energetic and Nuclear Research, Sao Paulo, SP 05508-000, Brazil
Adriano Duatti
- Laboratory of Nuclear Medicine, Department of Clinical and Experimental Medicine, University of Ferrara, Ferrara, 44100, Italy
Emiko Muramoto
- Radiopharmacy Center, Institute of Energetic and Nuclear Research, Sao Paulo, SP 05508-000, Brazil
Salomao Faintuch
- Department of Radiology, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA
Charles J. Smith
- Department of Radiology, Missouri University Research Reactor, and Radiopharmaceutical Sciences Institute, University of Missouri-Columbia, The Harry S. Truman Memorial Veterans' Hospital, Columbia, MO 65201, USA

Received 22 July 2007; received in revised form 17 February 2008; accepted 28 February 2008.

Abstract

Introduction

Radionuclide imaging can be a useful tool for the diagnosis of prostate cancer. Bombesin (BBN) is a molecule with high affinity for gastrin releasing peptide (GRP) receptors which are over-expressed in that tumor. This report compares ^99mTc-HYNIC-βAla-BBN(7-14)NH2 [^99mTc-HYNIC-BBN] and ^99mTc≡N(PNP6)-Cys-βAla-BBN(7-14)NH2 [^99mTcN(PNP6)-Cys-BBN] with regard to labeling procedures as well as in vitro and in vivo evaluation (biodistribution and scintigraphic imaging).

Methods

Peptide synthesis was performed in an automated peptide synthesizer. HYNIC-BBN was radiolabeled with pertechnetate using tricine and ethylenediamine diacetic acid (EDDA) as coligands. Cys- BBN was radiolabeled in a two-step procedure with the preparation of the precursor ^99mTc-Nitrido first and then introducing diphosphine (PNP6). Radiochemical evaluation of conjugates, as well as studies of stability, transchelation toward cysteine, and partition coefficient were done. Biological studies included internalization, biodistribution in healthy animals and in animals bearing PC3 cancer cells with acquisition of images from the tumor-bearing animals.

Results

Both complexes showed a high radiochemical yield along with good stability. Biodistribution studies pointed out strong renal excretion for the former complex due to its hydrophilic profile and marked hepatobiliary excretion for the latter, corresponding to observed lipophilicity. Tumor uptake was higher for ^99mTc-HYNIC-BBN and the same occurred with internalization findings, which exceeded those of ^99mTcN(PNP6)-BBN. Blocking studies in mice bearing PC-3 tumor cells revealed significantly reduced pancreas and tumor uptake, demonstrating receptor specificity of the conjugates.

Conclusion

The best radiotracer was ^99mTc-HYNIC-BBN on the basis of high radiochemical yield, fast radiolabeling procedure without need for a purification step, and more consistent tumor uptake.

Keywords: Bombesin analogs, technetium 99m (^99mTc)-HYNIC-BBN, Prostate cancer, ^99mTcN(PNP6)-Cys-BBN