1. Evaluation of three different families of bombesin receptor radioantagonists for targeted imaging and therapy of gastrin releasing peptide receptor (GRP-R) positive tumors
Rosalba Mansi, Keelara Abiraj, Xuejuan Wang, Maria Luisa Tamma, Eleni Gourni, Renzo Cescato, Sandra Berndt, Jean Claude Reubi, Helmut R Maecke J Med Chem. 2015 Jan 22;58(2):682-91. doi: 10.1021/jm5012066. Epub 2014 Dec 17.
Two new classes of radiolabeled GRP receptor antagonists are studied and compared with the well-established statine-based receptor antagonist DOTA-4-amino-1-carboxymethylpiperidine-d-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2 (RM2, 1; DOTA:1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid; Sta:(3S,4S)-4-amino-3-hydroxy-6-methylheptanoic acid). The bombesin-based pseudopeptide DOTA-4-amino-1-carboxymethylpiperidine-d-Phe-Gln-Trp-Ala-Val-Gly-His-Leuψ(CHOH-CH2)-(CH2)2-CH3 (RM7, 2), and the methyl ester DOTA-4-amino-1-carboxymethylpiperidine-d-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-OCH3 (ARBA05, 3) analogues are labeled with (111)In and evaluated in vitro in PC-3 cell line and in vivo in PC-3 tumor-bearing nude mice. Antagonist potency was assessed by immunofluorescence-based receptor internalization and Ca(2+) mobilization assays. The conjugates showed good binding affinity, the IC50 value of 2 (3.2 ± 1.8 nM) being 2 and 10 times lower than 1 and 3. Compared to (111)In-1, (111)In-2 showed higher uptake in target tissues such as pancreas (1.5 ± 0.5%IA/g and 39.8 ± 9.3%IA/g at 4 h, respectively), whereas the compounds had similar tumor uptake (11.5 ± 2.4%IA/g and 11.8 ± 3.9%IA/g at 4h, respectively). The displacement of the radioligand in vivo was different in different receptor positive organs and depended on the displacing peptide.
3. New potential renin inhibitors with dipeptide replacements in the molecule
Iwona Winiecka, Jadwiga Dudkiewicz-Wilczyńska, Iza Roman, Ryszard Paruszewski Acta Pol Pharm. 2010 Jul-Aug;67(4):367-74.
A series of eight non-peptidic potential renin inhibitors have been designed and synthesized. All of them contain dipeptide replacement: (3S,4S)-4-amino-5-cyclohexyl-3-hydroxypentanoic acid (ACHPA) in their molecules. Four among them comprise two additional analogs of dipeptide: (3S,4S)-4-amino-3-hydroxy-5-phenylpentanoic acid (AHPPA) and (3S,4S)-4-amino-3-hydroxy-6-methylheptanoic acid (statine, Sta). All of the synthesized compounds contain also hydrophobic portions to receive a moderate lipophilicity of the molecules. Inhibitory activity of the compounds was measured in vitro by I-IPLC determination of Leu-Val-Tyr-Ser released from the N-acetyltetradecapeptide substrate by renin in the presence of the inhibitor. Asp-alpha(OEt)-(S,S)-ACHPA-epsilonAhx-Iaa (23) shows inhibitory activity (7%) at the concentration of 1.0 x 10(-2) M. The other synthesized compounds show no inhibitory activity up to this concentration.
