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

New beta-adrenergic receptor antagonists, 2-(R)-(+)- and l-oxy)-3-[[1- (fluoromethyl)ethyl]amino]-2-propanol ((S)- and (R)-fluorocarazolols), were labeled with fluorine-18 at the no-carrier-added level by reduct ive alkylation of desisopropylcarazolol (4-(2-hydroxy-3-amino-1-propox y)carbazole) with [F-18]fluoroacetone. The latter was prepared by nucl eophilic 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 val ues of(S)- and (R)-fluorocarazolol for the beta-adrenergic receptor we re measured in a rat heart preparation to be K-D= 68 and 1128 pM, resp ectively. Biodistribution experiments in mice demonstrated specific be ta-adrenergic receptor binding of (S)-[F-18]fluorocarazolol. (R)-[F-18 ]fluorocarazolol showed no observable specific binding to beta-recepto rs in vivo. The uptake of (R)-[F-18]fluorocarazolol may therefore be u sed as an estimation of nonspecific binding. Positron emission tomogra phy images of pigs showed receptor-specific uptake of(S)-[F-18]fluoroc arazolol in the heart and lung. Washout of dissociated ligand from the tissue was observed only after 70 min postinjection. The maximum rati o of specific to nonspecific uptake in pig heart and lung was ca. 10 a t 150 min postinjection. Observed levels of fluorocarazolol metabolite s in mouse and pig blood were relatively low and remained fairly const ant 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.