Synthesis and in vivo imaging properties of [11C]befloxatone: a novel highly potent positron emission tomography ligand for mono-amine oxidase-A.

Befloxatone (1, (5R)-5-(methoxymethyl)-3-[4-[(3R)-4,4,4-trifluoro-3-hydroxybutoxy]phenyl]-2-oxazolidinone) is an oxazolidinone derivative belonging to a new generation of reversible and selective mono-amine oxidase-A (MAO-A) inhibitors. In vitro and ex vivo studies have demonstrated that befloxatone is a potent, reversible and competitive MAO-A inhibitor with potential antidepressant properties. Befloxatone (1) was labelled with carbon-11 (t(12): 20.4 min) using [(11)C]phosgene as reagent. Typically, starting from a 1.2 Ci (44.4 GBq) cyclotron-produced [(11)C]CH(4) batch, 150-300 mCi (5.55-11.10 GBq) of [(11)C]befloxatone ([(11)C]-1) with a radiochemical- and chemical purity of more than 99% were routinely obtained within 20 min of radiosynthesis (including HPLC purification) with specific radioactivities of 500-2000 mCi/micromol (18.5-74.0 GBq/micromol). The results obtained in vivo with carbon-11-labelled befloxatone not only confirm the biochemical and pharmacological profile of befloxatone found in rodent and in human tissues but also point out [(11)C]befloxatone as an excellent tool for the assessment of MAO-A binding sites using positron emission tomography, a high-resolution, sensitive, non-invasive and quantitative imaging technique.

Mapping the cerebral monoamine oxidase type A: positron emission tomography characterization of the reversible selective inhibitor [11C]befloxatone.

Befloxatone is a competitive and reversible inhibitor of monoamine oxidase-A (MAOI-A). The aim of the study was to characterize the in vivo properties of [(11)C]befloxatone and to validate its use as a ligand for the study of MAO-A by positron emission tomography (PET). PET studies were performed in baboons after i.v. injection of [(11)C]befloxatone (551 +/- 70 MBq, i.e.14.9 +/- 1.9 mCi). [(11)C]Befloxatone enters rapidly in the brain with a maximum uptake at 30 min. Brain concentration of the tracer is high in thalamus, striatum, pons and cortical structures (1.5-1.8% of injected dose per 100 ml of tissue), and lower in cerebellum (1.07% injected dose/100 ml). Nonsaturable uptake, obtained after a pretreatment with a high dose of nonlabeled befloxatone (0.4 mg/kg), is very low and represents only 3% of the total uptake. Brain uptake of [(11)C]befloxatone is not altered by a pretreatment of a high dose with lazabemide (0.5 mg/kg i.v.), a selective MAOI-B but is completely blocked by a pretreatment with moclobemide (MAOI-A; 10 mg/kg). This confirms, in vivo, the selectivity of befloxatone for type A MAO. [(11)C]Befloxatone brain radioactivity was displaced by administration of unlabeled befloxatone (30 min after the tracer injection). The displacement of the tracer from its binding sites is dose-dependent, with an ID(50) of 0.02 mg/kg for all studied structures. These results indicate that [(11)C]befloxatone will be an excellent probe for the study of MAO-A in humans using PET.

In vivo quantification of myocardial dihydropyridine binding sites: a PET study in dogs.

UNLABELLED: Abnormalities in myocardial L-type Ca(2+) channel abundance and function have been described in cardiac hypertrophy and failure. In vivo quantification of the density of these channels using PET and an adequate ligand would provide new insights into cardiac disease. METHODS: The dihydropyridine L-type Ca(2+) channel antagonist S12968 (3-ethyl 5-methyl (-)-2-[(2-(2-aminoethoxy)ethoxy)methyl]-4-(2,3-dichlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate) was labeled with (11)C and injected in various amounts (5-23 nmol), 20 or 30 min apart, into dogs. This protocol allowed a separate evaluation of the density of binding sites (B(max)) as well as association and dissociation rate constants. The parameters were calculated using a nonlinear mathematic model. RESULTS: Using the multiinjection approach, a complete model describing interactions between S12968 and the dihydropyridine binding sites was obtained. B(max) was found to be 19.2 +/- 3.3 pmol x mL(-1) of tissue. Association and dissociation constants (estimated by K(on)/VR and K(d)VR, respectively) were found to be 0.015 +/- 0.01 mL x pmol(-1) x min(-1) and 4.2 +/- 2.2 nmol x mL(-1), respectively. CONCLUSION: The present data suggest that it is possible to measure myocardial dihydropyridine binding site density with a single radiosynthesis and a simple PET protocol that is not time consuming (75 min for the total examination, including transmission and emission scans). This methodology can be useful to investigate human cardiac disease in vivo.