title: Synthesis and biological evaluation of tricarbonyl Re(I) and Tc(I) complexes anchored by poly(azolyl)borates: application on the design of radiopharmaceuticals for the targeting of 5-HT1A receptors.
abstract: The building blocks fac-[(99m)Tc{kappa(3)-HB(tim(Me))(3)}(CO)(3)] and fac-[(99m)Tc{kappa(3)-R(mu-H)B(tim(Me))(2)}(CO)(3)] [R is H (4a), Ph (5a); tim(Me) is 2-mercapto-1-methylimidazolyl] were obtained almost quantitatively by reacting fac-[(99m)Tc(CO)(3)(H(2)O)(3)](+) with the corresponding scorpionate. These compounds cross the intact blood-brain barrier in mice, with significant retention in the case of 4a and 5a. Using 4a as the lead structure, we have synthesized the functionalized complexes fac-[M{kappa(3)-H(mu-H)B(tim(Bu-pip))(2)}(CO)(3)] [M is Re (8), (99m)Tc (8a); tim(Bu-pip) is methyl[4-((2-methoxyphenyl)-1-piperazinyl)butyl](2-mercapto-1-methylimidazol-5-yl)methanamide] and fac-[M{kappa (3)-H(mu-H)B(tim(Me))(tim(Bu-pip))}(CO)(3)] [M is Re (9), (99m)Tc (9a)] and evaluated their potential as radioactive probes for the targeting of brain 5-HT(1A) serotonergic receptors. The Re complexes exhibit excellent affinity [IC(50)=0.172 +/- 0.003 nM (8); IC(50)=0.65 +/- 0.01 nM (9)] for the 5-HT(1A) receptor. The radioactive congeners ((99m)Tc) have shown an initial brain uptake of 1.38 +/- 0.46%ID g(-1) (8a) and 0.43 +/- 0.12%ID g(-1) (9a), but suffer from a relatively fast washout.
authors.affiliation: Departamento de Química, ITN, Estrada Nacional 10, 2686-953 Sacavém Codex, Portugal.
authors.forename: Raquel
authors.initials: R
authors.lastname: Garcia
authors.forename: Lurdes
authors.initials: L
authors.lastname: Gano
authors.forename: Leonor
authors.initials: L
authors.lastname: Maria
authors.forename: António
authors.initials: A
authors.lastname: Paulo
authors.forename: Isabel
authors.initials: I
authors.lastname: Santos
authors.forename: Hartmut
authors.initials: H
authors.lastname: Spies
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier; D002851:Chromatography, High Pressure Liquid; D015195:Drug Design; D005260:Female; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D011869:Radioligand Assay; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D044282:Receptor, Serotonin, 5-HT1A / Q000187:drug effects*; D012211:Rhenium / Q000737:chemistry*; D021241:Spectrometry, Mass, Electrospray Ionization; D013055:Spectrophotometry, Infrared; D013667:Technetium / Q000737:chemistry*; D014018:Tissue Distribution
chemical_list: D019275:Radiopharmaceuticals; D044282:Receptor, Serotonin, 5-HT1A; D012211:Rhenium; D013667:Technetium