Evolution of bombesin conjugates for targeted PET imaging of tumors Journal Article
| Authors: | Zhang, H.; Abiraj, K.; Thorek, D. L. J.; Waser, B.; Smith-Jones, P. M.; Honer, M.; Reubi, J. C.; Maecke, H. R. |
| Article Title: | Evolution of bombesin conjugates for targeted PET imaging of tumors |
| Abstract: | Bombesin receptors are under intense investigation as molecular targets since they are overexpressed in several prevalent solid tumors. We rationally designed and synthesized a series of modified bombesin (BN) peptide analogs to study the influence of charge and spacers at the N-terminus, as well as amino acid substitutions, on both receptor binding affinity and pharmacokinetics. This enabled development of a novel 64/67Cu-labeled BN peptide for PET imaging and targeted radiotherapy of BN receptor-positive tumors. Our results show that N-terminally positively charged peptide ligands had significantly higher affinity to human gastrin releasing peptide receptor (GRPr) than negatively charged or uncharged ligands (IC 50: 3.2±0.5 vs 26.3±3.5 vs 41.5±2.5 nM). The replacement of Nle 14 by Met, and deletion of D-Tyr 6, further resulted in 8-fold higher affinity. Contrary to significant changes to human GRPr binding, modifications at the N-terminal and at the 6 th, 11 th, and 14 th position of BN induced only slight influences on affinity to mouse GRPr. [Cu II]-CPTA-[βAla 11] BN(7-14) ([Cu II]-BZH7) showed the highest internalization rate into PC-3 cells with relatively slow efflux because of its subnanomolar affinity to GRPr. Interestingly, [ 64/67Cu]-BZH7 also displayed similar affinities to the other 2 human BN receptor subtypes. In vivo studies showed that [ 64/67Cu]-BZH7 had a high accumulation in PC-3 xenografts and allowed for clear-cut visualization of the tumor in PET imaging. In addition, a CPTA-glycine derivative, forming a hippurane-type spacer, enhanced kidney clearance of the radiotracer. These data indicate that the species variation of BN receptor plays an important role in screening radiolabeled BN. As well, the positive charge from the metallated complex at the N-terminal significantly increases affinity to human GRPr. Application of these observations enabled the novel ligand [ 64/67Cu]-BZH7 to clearly visualize PC-3 tumors in vivo. This study provides a strong starting point for optimizing radiopeptides for targeting carcinomas that express any of the BN receptor subtypes. © 2012 Zhang et al. |
| Keywords: | controlled study; unclassified drug; nonhuman; positron emission tomography; radiopharmaceuticals; binding affinity; neoplasms; mouse; animals; mice; animal tissue; amino acid substitution; animal experiment; animal model; protein binding; in vivo study; drug structure; in vitro study; tumor xenograft; cell line, tumor; drug receptor binding; amino terminal sequence; drug distribution; isotope labeling; tissue distribution; mice, nude; prostate tumor; positron-emission tomography; radiopharmaceutical agent; transplantation, heterologous; drug clearance; drug half life; ic 50; drug tumor level; drug stability; tumor diagnosis; internalization; copper radioisotopes; conjugate; bombesin; 1,4,7,10 tetraazacyclododecane 1,4,7,10 tetraacetic acid gamma aminobutyric acid dextrotryrosinylglutaminyltryptophanylalanylvalylalanylhistidylleucylnorleucylamine cu 64; 1,4,7,10 tetraazacyclododecane 1,4,7,10 tetraacetic acid gamma aminobutyric acid dextrotryrosinylglutaminyltryptophanylalanylvalylalanylhistidylleucylnorleucylamine cu 67; 1,4,7,10 tetraazacyclododecane 1,4,7,10 tetraacetic acid gamma aminobutyric acid dextrotryrosinylglutaminyltryptophanylalanylvalylalanylhistidylleucylnorleucylamine in 111; 4 (1,4,8,11 tetraazacyclotetradec 1 yl)methyl benzoic acid dextrotyrosylglutaminyltryptophanylalanylvalylalanylhistidylleucylmethionylamine cu 64; 4 (1,4,8,11 tetraazacyclotetradec 1 yl)methyl benzoic acid dextrotyrosylglutaminyltryptophanylalanylvalylalanylhistidylleucylmethionylamine cu 67; 4 (1,4,8,11 tetraazacyclotetradec 1 yl)methyl benzoic acid dextrotyrosylglutaminyltryptophanylalanylvalylalanylhistidylleucylnorleucylamine cu 64; 4 (1,4,8,11 tetraazacyclotetradec 1 yl)methyl benzoic acid dextrotyrosylglutaminyltryptophanylalanylvalylalanylhistidylleucylnorleucylamine cu 67; 4 (1,4,8,11 tetraazacyclotetradec 1 yl)methyl benzoic acid glutaminyltryptophanylalanylvalylalanylhistidyllecuylmethionylamine cu 64; 4 (1,4,8,11 tetraazacyclotetradec 1 yl)methyl benzoic acid glutaminyltryptophanylalanylvalylalanylhistidyllecuylmethionylamine cu 67; bombesin receptor; kinesis; receptors, bombesin |
| Journal Title: | PLoS ONE |
| Volume: | 7 |
| Issue: | 9 |
| ISSN: | 1932-6203 |
| Publisher: | Public Library of Science |
| Date Published: | 2012-01-01 |
| Start Page: | e44046 |
| Language: | English |
| DOI: | 10.1371/journal.pone.0044046 |
| PROVIDER: | scopus |
| PMCID: | PMC3443097 |
| PUBMED: | 23024746 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 1 October 2012" - "Source: Scopus" |
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