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J Nucl Med. 2008; 49 (Supplement 1):331P
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Oncology-Basic Science: Therapy, Metrics & Intervention

Therapy, Metrics & Intervention Posters

SAR and in vivo studies on Lu-177 labeled bombesin derivatives

Sandra Borkowski1, Ananth Srinivasan1, Keith Graham1 and Ludger M. Dinkelborg1

1 Research Laboratories, Bayer Schering Pharma AG, Berlin, Germany

1404

Objectives: Gastrin-releasing peptide receptors (GRPr) overexpressed in a variety of cancers can be efficiently targeted by bombesin (BN) peptides and thereby deliver therapeutic isotopes such as Lu-177 for radiopeptide therapy. Structure-activity-relationship and in vivo studies were carried out with Lu-177-DOTA-conjugated BN peptide derivatives comprising different spacer lengths and stabilizing aminoacid analogs to identify the most promising candidate for radiotherapy of prostate tumors.

Methods: Binding affinity of seven DOTA-conjugated BN derivatives was tested via scintillation proximity assay competing against I-125-Tyr4-BN. Lu-177 labeled peptides were investigated in vitro for human plasma stability and internalization in PC-3 cells. Biodistribution experiments and planar scintigraphy were carried out in PC-3 prostate tumor bearing mice.

Results: Six peptides revealed high affinity for the GRPr (IC50 0.21-1.60 nM) whereas internalization varied between 100-1,500 fmol/ mg cell protein and decreased with increasing spacer length. Plasma stability showed degradation between 20-99% within 4 h inversely correlated to spacer length and presenting Lu-177-DOTA-5Ava-Gln-Trp-Ala-Val-betaAla-His-Tha-Leu-NH2 as the most stable BN analog. Subsequently this peptide had the highest tumor uptake (2.58% ID/g) at 4 h p.i. and visualized well PC-3 tumors via planar scintigraphy.

Conclusions: A short 5Ava-linker and a peptide sequence containing a stabilizing aminoacid analog resulted in the most promising in vitro and in vivo characteristics as compared to non-linker or increasing spacer lengths. Lu-177-DOTA-5Ava-Gln-Trp-Ala-Val-betaAla-His-Tha-Leu-NH2 could be identified as the most promising BN peptide to deliver Lu-177 for radiotherapy of prostate tumors.





This Article
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Right arrow Email this article to a friend
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Right arrow Alert me to new issues of the journal
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Right arrow Articles by Borkowski, S.
Right arrow Articles by Dinkelborg, L. M.
PubMed
Right arrow Articles by Borkowski, S.
Right arrow Articles by Dinkelborg, L. M.