Novel 111In-labelled bombesin analogues for molecular imaging of prostate tumours

Purpose It has been shown that some primary human tumours and their metastases, including prostate and breast tumours, overexpress gastrin- releasing peptide ( GRP) receptors. Bombesin ( BN) is a neuropeptide with a high affinity for these GRP receptors. We demonstrated successful scintigraphic visualisation of BN receptor- positive tumours in preclinical studies using the radiolabelled BN analogue [ In-111- DTPA- Pro(1), Tyr(4)] BN. However, the receptor affinity as well as the serum stability of this analogue leave room for improvement. Therefore new 111In- labelled BN analogues were synthesised and evaluated in vitro and in vivo. Methods and results The receptor affinity of the new BN analogues was tested on human GRP receptor- expressing prostate tumour xenografts and rat colon sections. Analogues with high receptor affinity ( low nM range) were selected for further evaluation. Incubation in vitro of GRP receptorexpressing rat CA20948 and human PC3 tumour cells with the 111In- labelled analogues resulted in rapid receptormediated uptake and internalisation. The BN analogue with the best receptor affinity and in vitro internalisation characteristics, Cmp 3 ([ In-111- DTPA- ACMpip(5), Tha(6), beta Ala(11), Tha(13), Nle(14)] BN( 5 - 14)), was tested in vivo in biodistribution studies using rats bearing GRP receptor- expressing CA20948 tumours, and nude mice bearing human PC3 xenografts. Injection of 111In- labelled Cmp 3 in these animals showed high, receptor- mediated uptake in receptor- positive organs and tumours which could be visualised using planar gamma camera and microSPECT/ CT imaging. Conclusion With their enhanced receptor affinity and their rapid receptor- mediated internalisation in vitro and in vivo, the new BN analogues, and especially Cmp 3, are promising candidates for use in diagnostic molecular imaging and targeted radionuclide therapy of GRP receptorexpressing cancers.