title: Structure-activity relationship study towards non-peptidic positron emission tomography (PET) radiotracer for gastrin releasing peptide receptors: Development of [18F] (S)-3-(1H-indol-3-yl)-N-[1-[5-(2-fluoroethoxy)pyridin-2-yl]cyclohexylmethyl]-2-methyl-2-[3-(4-nitrophenyl)ureido]propionamide.
abstract: Gastrin-releasing peptide receptors (GRP-Rs, also known as bombesin 2 receptors) are overexpressed in a variety of human cancers, including prostate cancer, and therefore they represent a promising target for in vivo imaging of tumors using positron emission tomography (PET). Structural modifications of the non-peptidic GRP-R antagonist PD-176252 ((S)-1a) led to the identification of the fluorinated analog (S)-3-(1H-indol-3-yl)-N-[1-[5-(2-fluoroethoxy)pyridin-2-yl]cyclohexylmethyl]-2-methyl-2-[3-(4-nitrophenyl)ureido]propionamide ((S)-1m) that showed high affinity and antagonistic properties for GRP-R. This antagonist was stable in rat plasma and towards microsomal oxidative metabolism in vitro. (S)-1m was successfully radiolabeled with fluorine-18 through a conventional radiochemistry procedure. [18F](S)-1m showed high affinity and displaceable interaction for GRP-Rs in PC3 cells in vitro.
authors.affiliation: Dipartimento di Farmacia - Scienze del Farmaco, Università degli Studi di Bari Aldo Moro, Bari, Italy.
authors.forename: Enza
authors.initials: E
authors.lastname: Lacivita
authors.affiliation: Dipartimento di Farmacia - Scienze del Farmaco, Università degli Studi di Bari Aldo Moro, Bari, Italy.
authors.forename: Ermelinda
authors.initials: E
authors.lastname: Lucente
authors.affiliation: Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Chantal
authors.initials: C
authors.lastname: Kwizera
authors.affiliation: Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Ines F
authors.initials: IF
authors.lastname: Antunes
authors.affiliation: Dipartimento di Farmacia - Scienze del Farmaco, Università degli Studi di Bari Aldo Moro, Bari, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Niso
authors.affiliation: Dipartimento di Farmacia - Scienze del Farmaco, Università degli Studi di Bari Aldo Moro, Bari, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: De Giorgio
authors.affiliation: Dipartimento di Farmacia - Scienze del Farmaco, Università degli Studi di Bari Aldo Moro, Bari, Italy; BIOFORDRUG s.r.l., Spin-off, Università degli Studi di Bari Aldo Moro, Bari, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Perrone
authors.affiliation: Dipartimento di Farmacia - Scienze del Farmaco, Università degli Studi di Bari Aldo Moro, Bari, Italy; BIOFORDRUG s.r.l., Spin-off, Università degli Studi di Bari Aldo Moro, Bari, Italy.
authors.forename: Nicola A
authors.initials: NA
authors.lastname: Colabufo
authors.affiliation: Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Philip H
authors.initials: PH
authors.lastname: Elsinga
authors.affiliation: Dipartimento di Farmacia - Scienze del Farmaco, Università degli Studi di Bari Aldo Moro, Bari, Italy; BIOFORDRUG s.r.l., Spin-off, Università degli Studi di Bari Aldo Moro, Bari, Italy. Electronic address: marcello.leopoldo@uniba.it.
authors.forename: Marcello
authors.initials: M
authors.lastname: Leopoldo
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004355:Drug Stability; D005462:Fluorine Radioisotopes; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D008024:Ligands; D008862:Microsomes, Liver / Q000378:metabolism; D010084:Oxidation-Reduction; D010671:Phenylurea Compounds / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D018004:Receptors, Bombesin / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014364:Tryptophan / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: C000625532:3-(1H-indol-3-yl)-N-(1-(5-(2-fluoroethoxy)pyridin-2-yl)cyclohexylmethyl)-2-methyl-2-(3-(4-nitrophenyl)ureido)propionamide; D005462:Fluorine Radioisotopes; D007211:Indoles; D008024:Ligands; D010671:Phenylurea Compounds; D019275:Radiopharmaceuticals; D018004:Receptors, Bombesin; D014364:Tryptophan; C116774:PD 176252
keywords: G-protein coupled receptors; Gastrin-releasing peptide; Molecular imaging; Positron emission tomography; Prostate cancer