title: Development of 3,4-dihydroisoquinolin-1(2H)-one derivatives for the Positron Emission Tomography (PET) imaging of σ₂ receptors.
abstract: σ₂ Receptors are promising biomarkers for cancer diagnosis given the relationship between the proliferative status of tumors and their density. With the aim of contributing to the research of σ₂ receptor Positron Emission Tomography (PET) probes, we developed 2-[3-[6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl]propyl]-3,4-dihydroisoquinolin-1(2H)-one (3), with optimal σ₂ pharmacological properties and appropriate lipophilicity. Hence, 3 served as the lead compound for the development of a series of dihydroisoquinolinones amenable to radiolabeling. Radiosynthesis for compound 26, which displayed the most appropriate σ₂ profile, was developed and σ₂ specific binding for the corresponding [(18)F]-26 was confirmed by in vitro autoradiography on rat brain slices. Despite the excellent in vitro properties, [(18)F]-26 could not successfully image σ₂ receptors in the rat brain in vivo, maybe because of its interaction with P-gp. Nevertheless, [(18)F]-26 may still be worthy of further investigation for the imaging of σ₂ receptors in peripheral tumors devoid of P-gp overexpression.
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari ALDO MORO, Via Orabona 4, I-70125 Bari, Italy. Electronic address: carmen.abate@uniba.it.
authors.forename: Carmen
authors.initials: C
authors.lastname: Abate
authors.forename: Svetlana V
authors.initials: SV
authors.lastname: Selivanova
authors.forename: Adrienne
authors.initials: A
authors.lastname: Müller
authors.forename: Stefanie D
authors.initials: SD
authors.lastname: Krämer
authors.forename: Roger
authors.initials: R
authors.lastname: Schibli
authors.forename: Roberta
authors.initials: R
authors.lastname: Marottoli
authors.forename: Roberto
authors.initials: R
authors.lastname: Perrone
authors.forename: Francesco
authors.initials: F
authors.lastname: Berardi
authors.forename: Mauro
authors.initials: M
authors.lastname: Niso
authors.forename: Simon M
authors.initials: SM
authors.lastname: Ametamey
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D005462:Fluorine Radioisotopes / Q000737:chemistry / Q000378:metabolism; D006168:Guinea Pigs; D006801:Humans; D007546:Isoquinolines / Q000138:chemical synthesis / Q000737:chemistry; D008297:Male; D057054:Molecular Imaging; D015394:Molecular Structure; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000378:metabolism; D044263:Receptors, Serotonin, 5-HT1 / Q000378:metabolism; D017480:Receptors, sigma / Q000378:metabolism*
chemical_list: D005462:Fluorine Radioisotopes; D007546:Isoquinolines; D019275:Radiopharmaceuticals; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D017480:Receptors, sigma; C104425:serotonin 7 receptor; C106107:sigma-2 receptor
keywords: 1,3-di-o-tolyl-guanidine; 6,7-Dimethoxytetrahydroisoquinoline; BBB; CNS; Calcein-AM; DMEM; DTG; Dihydroisoquinolinone; Dulbecco's modified eagle medium; IP(3); MDCK-MDR1; Madin Darby canine kidney cells transfected with the human MDR1 gene; P(app); P-glycoprotein; P-gp; PET; PGRMC1; Positron Emission Tomography; acetoxymethylester of calcein; apparent permeability; blood–brain barrier; central nervous system; inositol 1,4,5-trisphosphate; progesterone receptor membrane component 1; σ receptors; σ(2) receptors PET probe