SYNTHESIS, BINDING-PROPERTIES, AND F-18 LABELING OF FLUOROCARAZOLOL, A HIGH-AFFINITY BETA-ADRENERGIC-RECEPTOR ANTAGONIST

New beta-adrenergic receptor antagonists, 2-(R)-(+)- and 2-(S)-(-)-1-(9H-earbazol-4-yl-oxy)-3-[[1-(fluoromethyl)ethyl]amino]-2-propanol ((S)- and (R)-fluorocarazolols), were labeled with fluorine-18 at the no-carrier-added level by reductive alkylation of desisopropylcarazolol (4-(2-hydroxy-3-amino-1-propoxy)carbazole) with [F-18]fluoroacetone. The latter was prepared by nucleophilic substitution of fluoride on acetol tosylate and may serve as a useful synthetic precursor for other radiotracers. The radiochemical yield of [F-18]fluorocarazolol (500-1200 Ci/mmol) from [F-18]fluoride was 40 +/- 10% at the end of the 45 min synthesis. Chiral HPLC showed >99% enantiomeric purity of 2-(S)- and 2-(R)- [F-18] fluorocarazolols. The log P of fluorocarazolol was 2.2 at pH 7.4. The in vitro K-D values of(S)- and (R)-fluorocarazolol for the beta-adrenergic receptor were measured in a rat heart preparation to be K-D= 68 and 1128 pM, respectively. Biodistribution experiments in mice demonstrated specific beta-adrenergic receptor binding of (S)-[F-18]fluorocarazolol. (R)-[F-18]fluorocarazolol showed no observable specific binding to beta-receptors in vivo. The uptake of (R)-[F-18]fluorocarazolol may therefore be used as an estimation of nonspecific binding. Positron emission tomography images of pigs showed receptor-specific uptake of(S)-[F-18]fluorocarazolol in the heart and lung. Washout of dissociated ligand from the tissue was observed only after 70 min postinjection. The maximum ratio of specific to nonspecific uptake in pig heart and lung was ca. 10 at 150 min postinjection. Observed levels of fluorocarazolol metabolites in mouse and pig blood were relatively low and remained fairly constant during the period from 10 to 180 min postinjection. These results indicate that (S)-(-)-[F-18]fluorocarazolol is of interest for use as a radiopharmaceutical for estimation of beta-adrenergic receptors with positron tomography.