Synthesis and labelling with 18F of an MK 801 analogue: [18F]5‐(β‐fluoruethyl)‐10,11‐dihydro‐5H‐dibenzocycloheptene‐5,10‐imine

Abstract

AbstractThe 5‐(β‐fluoro)ethyl analogue 1 of MK 801 2 was synthesized and labelled with 18F in order to visualize the NMDA receptors by positron emission tomography. A tosyloxy precursor 3 was synthesized in 8 steps from dibromodibenzosuberone; the nucleophilic substitution of the tosyl group of 3 by the K18F/Krytofix 2,2,2 complex in CH3CN gave [18F] 1 in 25% radiochemical yield with a specific activity of 40 GBq/μmol (1 Ci/μmol).The major excitatory amino acids in mammalian brain CNS, L.glutamate and L. aspartate, have a neurotoxic activity mediated through excitatory synaptic receptors such as N‐Methyl‐D‐Aspartate (NMDA) receptor subtype. These excitotoxic amino acids have been implicated in several brain damages associated with epilepsy, anoxia‐ischemia and hypoglycemia (1). MK 801 [(+)5‐methyl‐10,11‐dihydro‐5H‐dibenzo‐cycloheptene‐5,10‐imine] 2 is a potent and non‐competitive antagonist of NMDA (2). MK 801 was shown, in animal models, to protect against hypoxic‐ischemic damage and NMDA neurotoxicity (3, 4). These results may have important implications for the treatment in man of stroke and neurodegenerative disorders. In order to visualize the NMDA receptors by positron emission tomography, the synthesis and the labelling with fluorine 18 (β+, t½ = 110 min) of the 5‐(β fluoro(ethyl 1 analogue of MK 801 2 was undertaken (Scheme I).