title: In vivo imaging of cardiovascular endothelin receptors using the novel radiolabelled antagonist [18F]-SB209670 and positron emission tomography (microPET).
abstract: The aim of this study was to develop an F-labelled analogue of SB209670 with subnanomolar affinity for the endothelin receptor and to test whether it would have the required pharmacokinetic properties to permit binding and imaging of endothelin receptors in rat heart in vivo using small animal positron emission tomography (PET) imaging. [18F]-SB209670 could be produced in a total radiochemical yield of 14.9 +/- 3.8% in 162 +/- 7 minutes (n = 6). The radiochemical purity of the isolated radioligand was 99% and the specific activity was 100-150 GBq/micromol. In vitro characterization using ligand-binding assays demonstrated that [18F]-SB209670 bound with a single subnanomolar affinity to human heart tissue (n = 3) with a KD = 0.67 +/- 0.14 nM and a Bmax = 168.3 +/- 29.3 fmol/mg protein. The binding was time-dependent with a half-time (t(1/2)) for association of 3.8 minutes and an association rate constant (kobs) of 0.182 +/- 0.032/min. In vivo distribution in the rat was studied using microPET. Dynamic imaging revealed a fast clearance of [F]-SB209670 from the circulation by the liver, indicative of a high degree of metabolism. However, visualization of uptake in the rat heart was achievable and dynamic PET data together with the in vitro results suggest that [F]-SB209670 binds rapidly and primarily to endothelin-A receptors in the heart.
authors.affiliation: Clinical Pharmacology Unit, Addenbrooke's Hospital, Cambridge, UK. pjj20@medschl.cam.ac.uk
authors.forename: Peter
authors.initials: P
authors.lastname: Johnström
authors.forename: Tim D
authors.initials: TD
authors.lastname: Fryer
authors.forename: Hugh K
authors.initials: HK
authors.lastname: Richards
authors.forename: Olivier
authors.initials: O
authors.lastname: Barret
authors.forename: John C
authors.initials: JC
authors.lastname: Clark
authors.forename: Eliot H
authors.initials: EH
authors.lastname: Ohlstein
authors.forename: John D
authors.initials: JD
authors.lastname: Pickard
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Davenport
mesh_terms: D000818:Animals; D065130:Endothelin A Receptor Antagonists; D005462:Fluorine Radioisotopes; D006321:Heart / Q000000981:diagnostic imaging*; D006352:Heart Ventricles / Q000000981:diagnostic imaging / Q000378:metabolism; D006801:Humans; D007189:Indans / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D007275:Injections, Intravenous; D008099:Liver / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A / Q000378:metabolism*
chemical_list: D065130:Endothelin A Receptor Antagonists; D005462:Fluorine Radioisotopes; D007189:Indans; D019275:Radiopharmaceuticals; D044022:Receptor, Endothelin A; C087551:1H-Indene-2-carboxylic acid, 1-(1,3-benzodioxol-5-yl)-3-(2- (carboxymethoxy)-4-methoxyphenyl)-2,3-dihydro-5-propoxy-, (1S,2R,3S)-