Effect of DOTA position on melanoma targeting and pharmacokinetic properties of 111In-labeled lactam bridge-cyclized alpha-melanocyte stimulating hormone peptide.

Abstract

UNLABELLED:

The purpose of this study was to examine the effect of DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) position on melanoma targeting and pharmacokinetics of radiolabeled lactam bridge-cyclized alpha-melanocyte stimulating hormone (alpha-MSH) peptide.

METHOD:

A novel lactam bridge-cyclized alpha-MSH peptide, Ac-GluGlu-CycMSH[DOTA] {Ac-Glu-Glu-c[Lys-Nle-Glu-His-DPhe-Arg-Trp-Gly-Arg-Pro-Val-Lys(DOTA)]}, was synthesized using standard 9-fluorenylmethyloxycarbonyl (Fmoc) chemistry. DOTA was directly attached to the alpha-amino group of Lys in the cyclic ring, while the N-terminus of the peptide was acetylated to generate Ac-GluGlu-CycMSH[DOTA]. The MC1 receptor binding affinity of Ac-GluGlu-CycMSH[DOTA] was determined in B16/F1 melanoma cells. Melanoma targeting and pharmacokinetic properties of Ac-GluGlu-CycMSH[DOTA]-111In were determined in B16/F1 melanoma-bearing C57 mice and compared to that of 111In-DOTA-Gly-Glu-c[Lys-Nle-Glu-His-DPhe-Arg-Trp-Gly-Arg-Pro-Val-Asp] (111In-DOTA-GlyGlu-CycMSH; DOTA was coupled to the N-terminus of the peptide).

RESULTS:

Ac-GluGlu-CycMSH[DOTA] displayed 0.6 nM MC1 receptor binding affinity in B16/F1 cells. Ac-GluGlu-CycMSH[DOTA]-111In was readily prepared with greater than 95% radiolabeling yield. Ac-GluGlu-CycMSH[DOTA]-111In exhibited high tumor uptake (11.42 +/- 2.20% ID/g 2 h postinjection) and prolonged tumor retention (9.42 +/- 2.41% ID/g 4 h postinjection) in B16/F1 melanoma-bearing C57 mice. The uptake values for nontarget organs were generally low (<1.3% ID/g) except for the kidneys 2, 4, and 24 h postinjection.

CONCLUSIONS:

DOTA position exhibited profound effect on melanoma targeting and pharmacokinetic properties of Ac-GluGlu-CycMSH[DOTA]-111In, providing a new insight into the design of lactam bridge-cyclized peptide for melanoma imaging and therapy.

• Authors: Haixun Guo, Jianquan Yang, Fabio Gallazzi, Eric R Prossnitz, Larry A Sklar, Yubin Miao
• Journal: Bioconjugate chemistry (Bioconjug Chem) Vol. 20 Issue 11 Pg. 2162-8 (Nov 2009) ISSN: 1520-4812 [Electronic] United States
• PMID: 19817405 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Chelating Agents
• Heterocyclic Compounds, 1-Ring
• Indium Radioisotopes
• Lactams
• Radiopharmaceuticals
• 1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid
• alpha-MSH

Topics

• Animals
• Chelating Agents (chemistry)
• Drug Delivery Systems (methods)
• Drug Design
• Heterocyclic Compounds, 1-Ring (chemistry)
• Indium Radioisotopes (chemistry, pharmacokinetics)
• Kidney (metabolism)
• Lactams
• Melanoma, Experimental (drug therapy)
• Mice
• Mice, Inbred C57BL
• Pharmacokinetics
• Radiopharmaceuticals (administration & dosage, chemical synthesis, pharmacokinetics)
• Structure-Activity Relationship
• alpha-MSH (chemistry, pharmacokinetics)