[Tc-99m][Tc(N)PNP43]-Labeled RGD Peptides As New Probes for a Selective Detection of alpha v beta(3) Integrin: Synthesis, Structure-Activity and Pharmacokinetic Studies

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 alpha(v)beta(3). Herein, RGDechi and three truncated derivatives functionalized...

Full description

Saved in:
Bibliographic Details
Published inJournal of medicinal chemistry Vol. 61; no. 21; pp. 9596 - 9610
Main Authors Bolzati, Cristina, Salvarese, Nicola, Carpanese, Debora, Seraglia, Roberta, Melendez-Alafort, Laura, Rosato, Antonio, Capasso, Domenica, Saviano, Michele, Del Gatto, Annarita, Comegna, Daniela, Zaccaro, Laura
Format Journal Article
LanguageEnglish
Published WASHINGTON Amer Chemical Soc 08.11.2018
Subjects
Chemistry, Medicinal
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Science & Technology
BREAST-CANCER
MIXED-LIGAND COMPLEXES
IN-VITRO
ALPHA-V-INTEGRINS
ANALOGS
VITRONECTIN
BIOLOGICAL EVALUATION
RECEPTORS
EXPRESSION
METAL FRAGMENT
Online AccessGet full text

Cover

More Information
Summary: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 alpha(v)beta(3). Herein, RGDechi and three truncated derivatives functionalized with a cysteine (1-4) were synthesized and labeled with the [Tc-99m][Tc(N)PNP43]-synthon ([PNP43 = (CH3)(2)P(CH2)(2)N-(C2H4OCH3)(CH2)(2)P(CH3)(2)]) ((99m)Tc1-4) as a basis for selective integrin recognition. The pharmacological parameters of all radiolabeled peptides were assessed along with the pharmaco-kinetic profiles of the most promising (99m)Tc1 and (99m)Tc2 compounds both on healthy and melanoma-bearing mice. Their metabolism and metabolite identification are also reported. (99m)Tc1-2 are able to discriminate between endogenously expressed integrins alpha(v)beta(3) and alpha(v)beta(5) 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 alpha(v)beta(3) expression by SPECT.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.8b01075