Novel 111In-labelled bombesin analogues for molecular imaging of prostate tumours.
OBJECTIVE
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 [(111)In-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 (111)In-labelled BN analogues were synthesised and evaluated in vitro and in vivo.


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 receptor-expressing rat CA20948 and human PC3 tumour cells with the (111)In-labelled analogues resulted in rapid receptor-mediated uptake and internalisation. The BN analogue with the best receptor affinity and in vitro internalisation characteristics, Cmp 3 ([(111)In-DTPA-ACMpip(5),Tha(6),betaAla(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 (111)In-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.


CONCLUSIONS
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 receptor-expressing cancers.
de Visser
M
M
Department of Nuclear Medicine, Erasmus MC, 3015 GD Rotterdam, The Netherlands. m.devisser@erasmusmc.nl
Bernard
H F
HF
Erion
J L
JL
Schmidt
M A
MA
Srinivasan
A
A
Waser
B
B
Reubi
J C
JC
Krenning
E P
EP
de Jong
M
M
D000818:Animals; D001839:Bombesin / Q000031:analogs & derivatives*; D045744:Cell Line, Tumor; D006801:Humans; D007205:Indium Radioisotopes / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008956:Models, Chemical; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000175:diagnosis / Q000000981:diagnostic imaging; D011471:Prostatic Neoplasms / Q000175:diagnosis* / Q000000981:diagnostic imaging*; D011485:Protein Binding; D011877:Radionuclide Imaging; D051381:Rats; D011917:Rats, Inbred Lew
D007205:Indium Radioisotopes; D001839:Bombesin