Melanoma targeting with [99mTc(N)(PNP3)]-labeled α-melanocyte stimulating hormone peptide analogs: Effects of cyclization on the radiopharmaceutical properties.
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.
Dipartimento di Scienze del Farmaco, University of Padova, Via Marzolo 5, 35131 Padova, Italy.
Davide
D
Carta
ICMATE-CNR, Corso Stati Uniti 4, 35127, Padova, Italy.
Nicola
N
Salvarese
Dipartimento di Scienze del Farmaco, University of Padova, Via Marzolo 5, 35131 Padova, Italy.
Nicolò
N
Morellato
Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Bautzner Landstrasse 400, 01328, Dresden, Germany.
Feng
F
Gao
Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Bautzner Landstrasse 400, 01328, Dresden, Germany.
Wiebke
W
Sihver
Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Bautzner Landstrasse 400, 01328, Dresden, Germany.
Hans Jurgen
HJ
Pietzsch
ICB-CNR, Via Marzolo 1, 35131 Padova, Italy.
Barbara
B
Biondi
ICB-CNR, Via Marzolo 1, 35131 Padova, Italy.
Paolo
P
Ruzza
ICMATE-CNR, Corso Stati Uniti 4, 35127, Padova, Italy.
Fiorenzo
F
Refosco
Dipartimento di Scienze Chirurgiche, Oncologiche e Gastroenterologiche, University of Padova, Via Gattamelata, 64, 35138 Padova.
Debora
D
Carpanese
Dipartimento di Scienze Chirurgiche, Oncologiche e Gastroenterologiche, University of Padova, Via Gattamelata, 64, 35138 Padova,; Istituto Oncologico Veneto IOV-IRCCS, Via Gattamelata, 64, 35128 Padova, Italy.
Antonio
A
Rosato
ICMATE-CNR, Corso Stati Uniti 4, 35127, Padova, Italy. Electronic address: bolzati@ieni.cnr.it.
Cristina
C
Bolzati
D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D003500:Cyclization; D004355:Drug Stability; D005260:Female; D008297:Male; D051379:Mice; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism*; D011854:Radiochemistry; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism*; D051381:Rats; D013667:Technetium / Q000737:chemistry*; D000521:alpha-MSH / Q000737:chemistry*
D010456:Peptides, Cyclic; D019275:Radiopharmaceuticals; D000521:alpha-MSH; D013667:Technetium
(99m)Tc; Imaging; Melanoma; Peptides; SPECT; α-MSH