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Rivista di Medicina Nucleare e Imaging Molecolare

A Journal on Nuclear Medicine and Molecular Imaging
Affiliated to the Society of Radiopharmaceutical Sciences and to the International Research Group of Immunoscintigraphy
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The Quarterly Journal of Nuclear Medicine and Molecular Imaging 2007 March;51(1):42-50

lingua: Inglese

New [99mTc]bombesin analogues with improved biodistribution for targeting gastrin releasing-peptide receptor-positive tumors

García Garayoa E. 1, Schweinsberg C. 1, Maes V. 2, Rüegg D. 1, Blanc A. 1, Bläuenstein P. 1, Tourwé D. A. 2, Beck-Sickinger A. G. 3, Schubiger P. A. 1

1 Paul Scherrer Institute Center for Radiopharmaceutical Science Villigen PSI, Switzerland
2 Department of Organic Chemistry Vrije Universiteit Brussel, Brussels, Belgium
3 Institute of Biochemistry University of Leipzig, Leipzig, Germany


Aim. Bombesin (BBS) receptors are potential targets for diagnosis and therapy of breast and prostate tumors. To overcome the rapid degradation of natural BBS some modifications were introduced at positions 13 and 14. Additionally, a spacer was inserted between the chelator and the binding sequence in order to further improve the in vivo uptake. The analogues were labeled with the [99mTc(CO)3]-core and tested.
Methods. Stability was analyzed in vitro in human plasma. Binding affinity and internalization were determined in vitro in prostate carcinoma PC-3 cells. Biodistribution studies and single photon emission computed tomography/X-ray computed tomography (SPECT/CT) imaging were performed in nude mice with PC-3 tumor xenografts.
Results. The changes introduced in the BBS(7-14) sequence substantially increased plasma stability. Affinity for gastrin releasing-peptide (GRP) receptors on PC-3 cells was comparable to that of the unmodified analogue with Kd<1 nM. The presence of a spacer in the molecule induced an increment in the in vivo uptake in pancreas and PC-3 xenografts (GRP receptor-positive tissues). The increase in pancreas and tumor uptake was higher when both spacer and stabilization are present in the same molecule. Moreover, in vivo uptake was highly specific. The tumor was clearly visualized by SPECT/CT.
Conclusion. The modifications in the BBS(7-14) sequence led to a higher plasma stability while binding affinity remained unaffected. Stabilization resulted in improved biodistribution with better tumor to non-tumor ratios. However, the insertion of a spacer had a greater influence on the biodistribution. Analogues with both spacer and stabilization are the most promising radiopharmaceuticals for targeting GRP receptor-positive tumors.

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