Synthesis and evaluation of [11C]AL-438 as a nonsteroidal glucocorticoid recepter ligand for imaging of brain glucocorticoid receptors

AIMS: Corticosteroids are implicated in neuropsychiatric disorders such as severe depression and anxiety. This work investigates the usefulness of nonsteroidal glucocorticoid receptor (GR) ligand [11C]AL-438 as PET ligand for imaging of brain GRs.
METHODS: [11C]AL-438 was synthesised by methylation of the corresponding O-desmethyl labelling precursor with [11C]MeI. Radiopharmacological characterisation of [11C]AL-438 was performed in Wistar rats using biodistribution studies, ex vivo autoradiography and small animal PET studies.
RESULTS: [11C]MeI was trapped in a DMF solution containing the O-desmethyl labelling precursor and NaOH as the base. The methylation reaction was accomplished within 5 min at 100°C. The total synthesis time including HPLC-purification was 40-45 min. [11C]AL-438 was obtained in radiochemical yields of 30-40% (decay-corrected) at a specific radioactivity of 15 to 20 GBq/µmol at the end of the synthesis. The radiochemical purity of [11C]AL-438 exceeded 98%.
Biodistribution studies in rats demonstrated a brain uptake of 1.6 ± 0.4% ID/g after 5 min p.i., which decreased to 0.6 ± 0.1% ID/g after 60 min. Brain to blood ratios at 5 min and 60 min p.i. were 3.0 and 1.0, respectively. The pituitary and adrenals as major GR-containing peripheral organs showed uptake of 2.4 ± 0.5% ID/g and 7.5 ± 1.5% ID/g after 5 min and of 1.8 ± 1.0% ID/g and 3.8 ± 0.6% ID/g after 60 min, respectively. The uptake in the pituitary and adrenals could not be reduced significantly by pretreatment with 10 mg/kg of corticosterone.
Ex vivo autoradiographic studies of [11C]AL-438 on rat brain 5 min after i.v. administration showed specific accumulation of radioactivity in regions rich of GR, such as hypothalamus and various nuclei of thalamus. CONCLUSION: The biodistribution and the brain autoradiographic data of [11C]AL-438 correlated with the expected pattern of GRs in rodents.