[Tc(N)PNP43]-Labeled RGD Peptides As New Probes for a Selective Detection of αvβ3 Integrin: Synthesis, Structure-Activity and Pharmacokinetic Studies

Cristina Bolzati, Nicola Salvarese, Debora Carpanese, Roberta Seraglia, Laura Meléndez-Alafort, Antonio Rosato, Domenica Capasso, Michele Saviano, Annarita Del Gatto, Daniela Comegna, Laura Zaccaro

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

New integrin-selective molecules suitable for therapeutic or imaging purposes are currently of interest in development of effective personalized medical platforms. RGDechi is a bifunctional peptide selective for integrin αvβ3. Herein, RGDechi and three truncated derivatives functionalized with a cysteine (1-4) were synthesized and labeled with the [99mTc][Tc(N)PNP43]-synthon ([PNP43 = (CH3)2P(CH2)2N(C2H4OCH3)(CH2)2P(CH3)2]) (99mTc1-4) as a basis for selective integrin recognition. The pharmacological parameters of all radiolabeled peptides were assessed along with the pharmacokinetic profiles of the most promising 99mTc1 and 99mTc2 compounds both on healthy and melanoma-bearing mice. Their metabolism and metabolite identification are also reported. 99mTc1-2 are able to discriminate between endogenously expressed integrins αvβ3 and αvβ5 and possess favorable pharmacokinetics characterized by low liver uptake and rapid elimination from nontarget tissues resulting in positive target-to-nontarget ratios. Results are encouraging; the presented construct can be considered the starting point for the development of agents for the selective detection of αvβ3 expression by SPECT.

Original languageEnglish
Pages (from-to)9596-9610
Number of pages15
JournalJournal of Medicinal Chemistry
Volume61
Issue number21
DOIs
Publication statusPublished - Nov 8 2018

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Integrins
Pharmacokinetics
Peptides
Single-Photon Emission-Computed Tomography
Cysteine
Melanoma
Pharmacology
arginyl-glycyl-aspartic acid
Liver
Therapeutics

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

[Tc(N)PNP43]-Labeled RGD Peptides As New Probes for a Selective Detection of αvβ3 Integrin : Synthesis, Structure-Activity and Pharmacokinetic Studies. / Bolzati, Cristina; Salvarese, Nicola; Carpanese, Debora; Seraglia, Roberta; Meléndez-Alafort, Laura; Rosato, Antonio; Capasso, Domenica; Saviano, Michele; Del Gatto, Annarita; Comegna, Daniela; Zaccaro, Laura.

In: Journal of Medicinal Chemistry, Vol. 61, No. 21, 08.11.2018, p. 9596-9610.

Research output: Contribution to journalArticle

Bolzati, C, Salvarese, N, Carpanese, D, Seraglia, R, Meléndez-Alafort, L, Rosato, A, Capasso, D, Saviano, M, Del Gatto, A, Comegna, D & Zaccaro, L 2018, '[Tc(N)PNP43]-Labeled RGD Peptides As New Probes for a Selective Detection of αvβ3 Integrin: Synthesis, Structure-Activity and Pharmacokinetic Studies', Journal of Medicinal Chemistry, vol. 61, no. 21, pp. 9596-9610. https://doi.org/10.1021/acs.jmedchem.8b01075
Bolzati, Cristina ; Salvarese, Nicola ; Carpanese, Debora ; Seraglia, Roberta ; Meléndez-Alafort, Laura ; Rosato, Antonio ; Capasso, Domenica ; Saviano, Michele ; Del Gatto, Annarita ; Comegna, Daniela ; Zaccaro, Laura. / [Tc(N)PNP43]-Labeled RGD Peptides As New Probes for a Selective Detection of αvβ3 Integrin : Synthesis, Structure-Activity and Pharmacokinetic Studies. In: Journal of Medicinal Chemistry. 2018 ; Vol. 61, No. 21. pp. 9596-9610.
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