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

• Published in: Journal of medicinal chemistry Vol. 61; no. 21; pp. 9596 - 9610
• Main Authors: Bolzati, Cristina, Salvarese, Nicola, Carpanese, Debora, Seraglia, Roberta, Meléndez-Alafort, Laura, Rosato, Antonio, Capasso, Domenica, Saviano, Michele, Del Gatto, Annarita, Comegna, Daniela, Zaccaro, Laura
• Format: Journal Article
• Language: English
• Published: United States 08.11.2018
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.8b01075

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 α β . Herein, RGDechi and three truncated derivatives functionalized with a cysteine (1-4) were synthesized and labeled with the [ Tc][Tc(N)PNP43]-synthon ([PNP43 = (CH ) P(CH ) N(C H OCH )(CH ) P(CH ) ]) ( Tc1-4) 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 Tc1 and Tc2 compounds both on healthy and melanoma-bearing mice. Their metabolism and metabolite identification are also reported. Tc1-2 are able to discriminate between endogenously expressed integrins α β and α β 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 α β expression by SPECT.