Radiosynthesis of [18F]Lu29-024: a potential PET ligand for brain imaging of the serotonergic 5-HT2 receptor.

In a previous work, Lu29-024 (2,5-dimethyl-3-(4-fluorophenyl)-1-(1-methyl-4-piperidinyl)-1H-indole), a selective 5-HT2A receptor antagonist with nanomolar affinity and high selectivity, was labeled with carbon-11 to evaluate its behavior as a potential PET ligand for the serotonergic 5-HT2A receptor in the central nervous system. Administration of this tracer to rats was followed by a good brain uptake, no brain labeled metabolites but no specific, regio-selective, binding at 20 and 40 min post injection. Despite this, the data noted at 20 and 40 min suggest that this tracer, if associated with a radioactive emitter with a longer half-life than that of carbon-11, could be useful for the quantification of 5HT2A receptors. For these reasons, we chose to label this compound, bearing a fluorine atom, with [18F]fluoride, in order to perform rat studies over a more prolonged time-scale. The precursor for the radiosynthesis of [18F]Lu29-024 was obtained in an overall yield of 20% by a multi-step synthesis including an acetonylation reaction followed by a Fisher indole reaction. The radiotracer was prepared by an aromatic substitution with activated [18F]fluoride followed by a decarbonylation reaction that employed Wilkinson's catalyst. The radiosynthesis of [18F]Lu29-024 required approximatively 110 min with an overall radiochemical yield of 20-35% and specific activities of 37GBq/micromol. Fluorine-labeled Lu29-024 may thus be envisaged as a potentially useful PET tracer that can be applied to a wide range of neurological and psychiatric diseases.

Radiosynthesis of [11C]Lu 29-024: a potential radiotracer for 5HT2 receptors PET studies.

For mapping 5-HT2 receptors in the central nervous system with positron emission tomography (PET), 2,5-dimethyl-3-(4-fluorophenyl)-1-(1-[11C]methyl-4-piperidinyl)-1H-indol e ([11C]Lu29-024) has been prepared. The precursor for the radiosynthesis of [11C]Lu29-024 was obtained in an overall yield of 53% by a convenient five-step synthesis; its reaction with [11C]methyl iodide afforded [11C]Lu29-024 in 35-50% radiochemical yield (decay corrected) in 45 to 50 min with a specific radioactivity ranging from 11 to 15 GBq/micromol. Following i.v. injections into rats, the analysis of plasma samples showed that the metabolism of [11C]Lu29-024 was rapid and extensive (60% of the original tracer was metabolized at 40 min). In contrast, only unmetabolized [11C]Lu29-024 could be detected in brain tissue. These biological results suggest that labeled metabolites have no access to brain tissue and further propose [11C]Lu29-024 as an interesting tool for PET studies of brain 5HT2 receptors.