title: Synthesis and preliminary evaluation of (S)-[11C]-exaprolol, a novel beta-adrenoceptor ligand for PET.
abstract: Positron-emitting beta-adrenoceptor ligands for the CNS could allow determination of changes in beta-adrenoceptor availability after treatment of patients with norepinephrine reuptake inhibitors or tricyclic antidepressants, and differential diagnosis between multiple sclerosis and other brain disorders in an early stage of the disease. No ligands suitable for this purpose are available for human use. In order to prepare a tracer for human studies, we labeled the biologically active enantiomer of the beta-blocker exaprolol with (11)C. Exaprolol has the appropriate lipophilicity (log P + 1.6) for entry of the CNS and is claimed to be a very potent beta-adrenoceptor antagonist. (S)-Desisopropyl-exaprolol was synthesized by reaction of 2-hexylphenol with (S)-glycidyl-nosylate followed by ring opening using ammonia gas. The desisopropyl precursor was reacted with (11)C-acetone in methanol to produce (S)-[(11)C]-exaprolol. Radiochemical purification was performed with RP-HPLC and was followed by Sep-Pak formulation. The labeled product was i.v. injected into male Wistar rats. Brain images were acquired using a microPET Focus 220 and the biodistribution of (11)C was assessed. The radiochemical yield of (S)-[(11)C]-exaprolol was 7% with a total synthesis time of 30 min. Specific activities were >10 GBq/micromol. Brain uptake of the tracer reached a maximum after 15 min. Standardized uptake values were moderate (0.5-0.9) but sufficient for imaging. However, beta-blockade (propranolol, 2.5mg/kg body weight) did not lower tracer uptake in any CNS region and washout from the brain was not accelerated when propranolol was administered 40 min after injection of (S)-[(11)C]-exaprolol. Tracer binding in lung, spleen and erythrocytes was lowered after beta-blockade, but the myocardial uptake of radioactivity was not affected. These data indicate that (S)-[(11)C]-exaprolol is not a suitable beta-adrenoceptor ligand for PET, probably because the in vivo affinity of exaprolol to beta-adrenoceptors is in the nM rather than the sub-nM range. The observed inhibition of tracer uptake in lung, spleen and erythrocytes seems due to an interaction of propranolol with amine transporters rather than beta-adrenoceptors.
authors.affiliation: Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands. a.van.waarde@ngmb.umcg.nl
authors.forename: Aren
authors.initials: A
authors.lastname: van Waarde
authors.forename: Janine
authors.initials: J
authors.lastname: Doorduin
authors.forename: Johan R
authors.initials: JR
authors.lastname: de Jong
authors.forename: Rudi A
authors.initials: RA
authors.lastname: Dierckx
authors.forename: Philip H
authors.initials: PH
authors.lastname: Elsinga
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging; D008297:Male; D049268:Positron-Emission Tomography; D011412:Propanolamines / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D011943:Receptors, Adrenergic, beta / Q000187:drug effects*; D014018:Tissue Distribution
chemical_list: D000319:Adrenergic beta-Antagonists; D011412:Propanolamines; D019275:Radiopharmaceuticals; D011943:Receptors, Adrenergic, beta; C012969:exaprolol