Melanoma targeting with alpha-melanocyte stimulating hormone analogs labeled with fac-[Tc-99m(CO)(3)](+): effect of cyclization on tumor-seeking properties
Autor(a) principal: | |
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Data de Publicação: | 2008 |
Outros Autores: | , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | https://hdl.handle.net/10216/82033 |
Resumo: | Early detection of primary melanoma tumors is essential because there is no effective treatment for metastatic melanoma. Several linear and cyclic radiolabeled alpha-melanocyte stimulating hormone (alpha-MSH) analogs have been proposed to target the melanocortin type 1 receptor (MC1R) overexpressed in melanoma. The compact structure of a rhenium-cyclized alpha-MSH analog (Re-CCMSH) significantly enhanced its in vivo tumor uptake and retention. Melanotan II (MT-II), a cyclic lactam analog of alpha-MSH (Ac-Nle-cyclo[Asp-His-DPhe-Arg-Trp-Lys]-NH2]), is a very potent and stable agonist peptide largely used in the characterization of melanocortin receptors. Taking advantage of the superior biological features associated with the MT-II cyclic peptide, we assessed the effect of lactam-based cyclization on the tumor-seeking properties of alpha-MSH analogs by comparing the pharmacokinetics profile of the (99)mTc-labeled cyclic peptide beta Ala-Nle-cyclo[Asp-His-DPhe-Arg-Trp-Lys]-NH2 with that of the linear analog beta Ala-Nle-Asp-His-DPhe-Arg-Trp-Lys-NH2 in melanoma-bearing mice. We have synthesized and coupled the linear and cyclic peptides to a bifunctional chelator containing a pyrazolyl-diamine backbone (pz) through the amino group of beta Ala, and the resulting pz-peptide conjugates were reacted with the fac-[Tc-99m(CO)(3)](+) moiety. The Tc-99m(CO)(3)-labeled conjugates were obtained in high yield, high specific activity, and high radiochemical purity. The cyclic Tc-99m(CO)(3)-labeled conjugate presents a remarkable internalization (87.1% of receptor-bound tracer and 50.5% of total applied activity, after 6 h at 37 degrees C) and cellular retention (only 24.7% released from the cells after 5 h) in murine melanoma B16F1 cells. A significant tumor uptake and retention was obtained in melanoma-bearing C57BL6 mice for the cyclic radioconjugate [9.26 +/- 0.83 and 11.31 +/- 1.83% ID/g at 1 and 4 h after injection, respectively]. The linear Tc-99m(CO)(3)-pz-peptide presented lower values for both cellular internalization and tumor uptake. Receptor blocking studies with the potent (Nle(4),DPhe(7))-alpha MSH agonist demonstrated the specificity of the radioconjugates to MC1R (74.8 and 44.5% reduction of tumor uptake at 4 h after injection for cyclic and linear radioconjugates, respectively). |
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Melanoma targeting with alpha-melanocyte stimulating hormone analogs labeled with fac-[Tc-99m(CO)(3)](+): effect of cyclization on tumor-seeking propertiesQuímicaChemical sciencesEarly detection of primary melanoma tumors is essential because there is no effective treatment for metastatic melanoma. Several linear and cyclic radiolabeled alpha-melanocyte stimulating hormone (alpha-MSH) analogs have been proposed to target the melanocortin type 1 receptor (MC1R) overexpressed in melanoma. The compact structure of a rhenium-cyclized alpha-MSH analog (Re-CCMSH) significantly enhanced its in vivo tumor uptake and retention. Melanotan II (MT-II), a cyclic lactam analog of alpha-MSH (Ac-Nle-cyclo[Asp-His-DPhe-Arg-Trp-Lys]-NH2]), is a very potent and stable agonist peptide largely used in the characterization of melanocortin receptors. Taking advantage of the superior biological features associated with the MT-II cyclic peptide, we assessed the effect of lactam-based cyclization on the tumor-seeking properties of alpha-MSH analogs by comparing the pharmacokinetics profile of the (99)mTc-labeled cyclic peptide beta Ala-Nle-cyclo[Asp-His-DPhe-Arg-Trp-Lys]-NH2 with that of the linear analog beta Ala-Nle-Asp-His-DPhe-Arg-Trp-Lys-NH2 in melanoma-bearing mice. We have synthesized and coupled the linear and cyclic peptides to a bifunctional chelator containing a pyrazolyl-diamine backbone (pz) through the amino group of beta Ala, and the resulting pz-peptide conjugates were reacted with the fac-[Tc-99m(CO)(3)](+) moiety. The Tc-99m(CO)(3)-labeled conjugates were obtained in high yield, high specific activity, and high radiochemical purity. The cyclic Tc-99m(CO)(3)-labeled conjugate presents a remarkable internalization (87.1% of receptor-bound tracer and 50.5% of total applied activity, after 6 h at 37 degrees C) and cellular retention (only 24.7% released from the cells after 5 h) in murine melanoma B16F1 cells. A significant tumor uptake and retention was obtained in melanoma-bearing C57BL6 mice for the cyclic radioconjugate [9.26 +/- 0.83 and 11.31 +/- 1.83% ID/g at 1 and 4 h after injection, respectively]. The linear Tc-99m(CO)(3)-pz-peptide presented lower values for both cellular internalization and tumor uptake. Receptor blocking studies with the potent (Nle(4),DPhe(7))-alpha MSH agonist demonstrated the specificity of the radioconjugates to MC1R (74.8 and 44.5% reduction of tumor uptake at 4 h after injection for cyclic and linear radioconjugates, respectively).20082008-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/10216/82033eng0949-825710.1007/s00775-007-0338-3Paula D RaposinhoCatarina XavierJoao D G CorreiaSoraia FalcaoPaula GomesIsabel Santosinfo:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-11-29T15:25:16Zoai:repositorio-aberto.up.pt:10216/82033Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-20T00:23:15.551325Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
Melanoma targeting with alpha-melanocyte stimulating hormone analogs labeled with fac-[Tc-99m(CO)(3)](+): effect of cyclization on tumor-seeking properties |
title |
Melanoma targeting with alpha-melanocyte stimulating hormone analogs labeled with fac-[Tc-99m(CO)(3)](+): effect of cyclization on tumor-seeking properties |
spellingShingle |
Melanoma targeting with alpha-melanocyte stimulating hormone analogs labeled with fac-[Tc-99m(CO)(3)](+): effect of cyclization on tumor-seeking properties Paula D Raposinho Química Chemical sciences |
title_short |
Melanoma targeting with alpha-melanocyte stimulating hormone analogs labeled with fac-[Tc-99m(CO)(3)](+): effect of cyclization on tumor-seeking properties |
title_full |
Melanoma targeting with alpha-melanocyte stimulating hormone analogs labeled with fac-[Tc-99m(CO)(3)](+): effect of cyclization on tumor-seeking properties |
title_fullStr |
Melanoma targeting with alpha-melanocyte stimulating hormone analogs labeled with fac-[Tc-99m(CO)(3)](+): effect of cyclization on tumor-seeking properties |
title_full_unstemmed |
Melanoma targeting with alpha-melanocyte stimulating hormone analogs labeled with fac-[Tc-99m(CO)(3)](+): effect of cyclization on tumor-seeking properties |
title_sort |
Melanoma targeting with alpha-melanocyte stimulating hormone analogs labeled with fac-[Tc-99m(CO)(3)](+): effect of cyclization on tumor-seeking properties |
author |
Paula D Raposinho |
author_facet |
Paula D Raposinho Catarina Xavier Joao D G Correia Soraia Falcao Paula Gomes Isabel Santos |
author_role |
author |
author2 |
Catarina Xavier Joao D G Correia Soraia Falcao Paula Gomes Isabel Santos |
author2_role |
author author author author author |
dc.contributor.author.fl_str_mv |
Paula D Raposinho Catarina Xavier Joao D G Correia Soraia Falcao Paula Gomes Isabel Santos |
dc.subject.por.fl_str_mv |
Química Chemical sciences |
topic |
Química Chemical sciences |
description |
Early detection of primary melanoma tumors is essential because there is no effective treatment for metastatic melanoma. Several linear and cyclic radiolabeled alpha-melanocyte stimulating hormone (alpha-MSH) analogs have been proposed to target the melanocortin type 1 receptor (MC1R) overexpressed in melanoma. The compact structure of a rhenium-cyclized alpha-MSH analog (Re-CCMSH) significantly enhanced its in vivo tumor uptake and retention. Melanotan II (MT-II), a cyclic lactam analog of alpha-MSH (Ac-Nle-cyclo[Asp-His-DPhe-Arg-Trp-Lys]-NH2]), is a very potent and stable agonist peptide largely used in the characterization of melanocortin receptors. Taking advantage of the superior biological features associated with the MT-II cyclic peptide, we assessed the effect of lactam-based cyclization on the tumor-seeking properties of alpha-MSH analogs by comparing the pharmacokinetics profile of the (99)mTc-labeled cyclic peptide beta Ala-Nle-cyclo[Asp-His-DPhe-Arg-Trp-Lys]-NH2 with that of the linear analog beta Ala-Nle-Asp-His-DPhe-Arg-Trp-Lys-NH2 in melanoma-bearing mice. We have synthesized and coupled the linear and cyclic peptides to a bifunctional chelator containing a pyrazolyl-diamine backbone (pz) through the amino group of beta Ala, and the resulting pz-peptide conjugates were reacted with the fac-[Tc-99m(CO)(3)](+) moiety. The Tc-99m(CO)(3)-labeled conjugates were obtained in high yield, high specific activity, and high radiochemical purity. The cyclic Tc-99m(CO)(3)-labeled conjugate presents a remarkable internalization (87.1% of receptor-bound tracer and 50.5% of total applied activity, after 6 h at 37 degrees C) and cellular retention (only 24.7% released from the cells after 5 h) in murine melanoma B16F1 cells. A significant tumor uptake and retention was obtained in melanoma-bearing C57BL6 mice for the cyclic radioconjugate [9.26 +/- 0.83 and 11.31 +/- 1.83% ID/g at 1 and 4 h after injection, respectively]. The linear Tc-99m(CO)(3)-pz-peptide presented lower values for both cellular internalization and tumor uptake. Receptor blocking studies with the potent (Nle(4),DPhe(7))-alpha MSH agonist demonstrated the specificity of the radioconjugates to MC1R (74.8 and 44.5% reduction of tumor uptake at 4 h after injection for cyclic and linear radioconjugates, respectively). |
publishDate |
2008 |
dc.date.none.fl_str_mv |
2008 2008-01-01T00:00:00Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
https://hdl.handle.net/10216/82033 |
url |
https://hdl.handle.net/10216/82033 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
0949-8257 10.1007/s00775-007-0338-3 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.source.none.fl_str_mv |
reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
instacron_str |
RCAAP |
institution |
RCAAP |
reponame_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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1799136148191182848 |