Melanoma targeting with [^99mTc(N)(PNP3)]-labeled α-melanocyte stimulating hormone peptide analogs: Effects of cyclization on the radiopharmaceutical properties

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• 作者：Davide Carta^a ; Nicola Salvarese^b ; ¹ ; Nicolò ; Morellato^a ; Feng Gao^c ; Wiebke Sihver^c ; Hans Jurgen Pietzsch^c ; Barbara Biondi^d ; Paolo Ruzza^d ; Fiorenzo Refosco^b ; Debora Carpanese^e ; Antonio Rosato^e ; ^f ; Cristina Bolzati^b ; ¹ ; ^{bolzati@ieni.cnr.it" class="auth_mail" title="E-mail the corresponding author}
• 关键词：99mTc ; α-MSH ; Melanoma ; Peptides ; SPECT ; Imaging
• 刊名：Nuclear Medicine and Biology
• 出版年：2016
• 出版时间：December 2016
• 年：2016
• 卷：43
• 期：12
• 页码：788-801
• 全文大小：1270 K

文摘

The purpose of this study was to evaluate the effect of cyclization on the biological profile of a [^99mTc(N)(PNP3)]-labeled α-melanocyte stimulating hormone peptide analog. A lactam bridge-cyclized H-Cys-Ahx-βAla³-c[Lys⁴-Glu-His-D-Phe-Arg-Trp-Glu¹⁰]-Arg¹¹-Pro-Val-NH₂ (NAP―NS2) and the corresponding linear H-Cys-Ahx-βAla-Nle-Asp-His-D-Phe-Arg-Trp-Gly-NH₂ (NAP―NS1) peptide were synthetized, characterized by ESI-MS spectroscopy and their melanocortin-1 receptor (MC1R) binding affinity was determined in B16/F10 melanoma cells. The consistent [^99mTc(N)(PNP3)]-labeled compounds were readily obtained in high specific activity and their stability and biological properties were assessed. As an example, the chemical identity of [^99mTc(N)(NAP–NS1)(PNP3)]⁺ was confirmed by carrier added experiments supported by radio/UV HPLC analysis combined with ESI(+)-MS.

Compared with the linear peptide, cyclization negatively affected the biological properties of NAP–NS2 peptide by reducing its binding affinity for MC1R and by decreasing the overall excretion rate of the corresponding [^99mTc(N)(PNP3)]-labeled peptide from the body as well as its in vivo stability.

[^99mTc(N)(NAP–NS1)(PNP3)]⁺ was evaluated for its potential as melanoma imaging probe in murine melanoma model.

Data from in vitro and in vivo studies on B16/F10 melanoma model of [^99mTc(N)(NAP–NS1)(PNP3)]⁺ clearly evidenced that the radiolabeled linear peptide keeps its biological properties up on the conjugation to the [^99mTc(N)(PNP3)]-building block. The progressive increase of the tumor-to-nontarget ratios over the time indicates a quite stable interaction between the radio-complex and the MC1R.