title: Arylamides hybrids of two high-affinity σ2 receptor ligands as tools for the development of PET radiotracers.
abstract: 1-Cyclohexyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]piperazine 1 (PB28) and 2-Methoxy-5-methyl-N-[4-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)butyl]benzamide 2 (RHM-1) represent leads for tumor diagnosis, given their high affinity at σ(2) receptors. With the purpose of obtaining good candidates for σ(2) PET tracers development, hybrid structures between 1 and 2 were designed. Excellent σ(1)/σ(2) selectivities were reached when 6,7-dimethoxytetrahydroisoquinoline was linked to an o-methoxy substituted arylamide (11a, 12a, 15a), and for these benzamides an intramolecular H-bond in the active conformation at the σ sites, was hypothesized. However these excellent σ(2) ligands were accompanied by interaction with P-gp, which may limit their use as σ(2) receptor PET agents when tumors overexpress P-gp. Compound 15a whose P-gp interaction was just moderate represents an interesting tool for the development of σ(2) PET tracers useful in tumors overexpressing P-gp.
authors.affiliation: Dipartimento Farmacochimico, Università degli Studi di Bari ALDO MORO, Via Orabona 4, I-70125 Bari, Italy. abate@farmchim.uniba.it
authors.forename: Carmen
authors.initials: C
authors.lastname: Abate
authors.forename: Savina
authors.initials: S
authors.lastname: Ferorelli
authors.forename: Marialessandra
authors.initials: M
authors.lastname: Contino
authors.forename: Roberta
authors.initials: R
authors.lastname: Marottoli
authors.forename: Nicola Antonio
authors.initials: NA
authors.lastname: Colabufo
authors.forename: Roberto
authors.initials: R
authors.lastname: Perrone
authors.forename: Francesco
authors.initials: F
authors.lastname: Berardi
mesh_terms: D000178:Acrylamides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D004285:Dogs; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D049268:Positron-Emission Tomography; D011869:Radioligand Assay; D017480:Receptors, sigma / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D000178:Acrylamides; D008024:Ligands; D017480:Receptors, sigma; C106107:sigma-2 receptor