title: Synthesis and evaluation of (S)-[18F]-fluoroethylcarazolol for in vivo beta-adrenoceptor imaging in the brain.
abstract: The beta-adrenergic receptor ligand (S)-4-(3-(2'-[18F]-fluoroethylamino)-2-hydroxypropoxy)-carbazol ((S)-[18F]-fluoroethylcarazolol) was prepared by reaction of [18F]-fluoroethylamine with the corresponding (S)-epoxide and was evaluated in rats by studying its pharmacokinetics and its binding profile both in vitro and in vivo. In vitro, (S)-fluoroethylcarazolol binds preferentially to beta-adrenoceptors (pK(i)=9.3 for beta(1) and 9.4 for beta(2)) and has less affinity to 5HT(1A) and 5HT(1D) receptors (pK(i)=6.7 and 5.2). In vivo, standard uptake values (SUVs) up to 0.63+/-0.07 in cortical regions were found after 60 min. Metabolites (90%) appeared within 10 min in plasma, whereas, in brain 70-75% parent compound was found after 60 min. Clearance from plasma occurred within 5 min. Cerebral uptake could be blocked by 'cold' fluoroethylcarazolol in every region, except medulla. Uptake was also blocked by propranolol and pindolol, but not by WAY 100635. ICI 89406 hardly lowered [18F] levels in brain. ICI 118551 reduced uptake of [18F] in cerebellum (mainly beta(2)) by 30%. Specific binding (tissue minus medulla values) in various brain regions corresponded with those observed for [18F]-fluorocarazolol (r(2)=0.95) and with in vitro beta-adrenoceptor densities (r(2)=0.76). Autoradiography using phosphor images of (S)-[18F]-fluoroethylcarazolol in rat brain showed the characteristic binding pattern of beta-antagonists, while propranolol treatment resulted in low and homogenous uptake. Regional tissue minus medulla values corresponded with in vitro beta-adrenoceptor densities (r(2)=0.77). We conclude that (S)-[18F]-fluoroethylcarazolol is a high affinity ligand that binds specifically to cerebral beta-adrenoceptors in vivo and may be of use for beta-adrenoceptor imaging in the brain with PET.
authors.affiliation: PET Center, Groningen University Hospital, P.O. Box 30001, 9700 RB Groningen, The Netherlands.
authors.forename: P
authors.initials: P
authors.lastname: Doze
authors.forename: A
authors.initials: A
authors.lastname: van Waarde
authors.forename: T J
authors.initials: TJ
authors.lastname: Tewson
authors.forename: W
authors.initials: W
authors.lastname: Vaalburg
authors.forename: P H
authors.initials: PH
authors.lastname: Elsinga
mesh_terms: D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000378:metabolism*; D002227:Carbazoles / Q000138:chemical synthesis* / Q000378:metabolism / Q000493:pharmacokinetics; D005461:Fluorine; D011412:Propanolamines / Q000138:chemical synthesis* / Q000378:metabolism / Q000493:pharmacokinetics; D051381:Rats; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D014055:Tomography, Emission-Computed
chemical_list: D002227:Carbazoles; D011412:Propanolamines; D011943:Receptors, Adrenergic, beta; C462379:fluoroethylcarazolol; D005461:Fluorine