The new PET imaging agent [11C]AFE is a selective serotonin transporter ligand with fast brain uptake kinetics

A new positron emission tomography (PET) radioligand for the serotonin transporter (SERT), [(11)C]2-[2-[[(dimethylamino)methyl]phenyl]thio]-5-(2-fluoroethyl)phenylamine ([(11)C]AFE, 12), was synthesized and evaluated in vivo in rats and baboons. [(11)C]AFE (12) was prepared from its monomethylamino precursor 11 by reaction with high specific activity [(11)C]methyl triflate. Radiochemical yield was 32+/-17% based on [(11)C]methyl triflate (n=6) and specific activity was 1670+/-864 Ci/mmol at end of synthesis (EOS, n=6). Binding assays indicated that AFE displays high affinity for SERT (K(i)=1.80 nM for hSERT) and lower affinity for norepinephrine transporter (K(i)=946 nM for hNET) or dopamine transporter (K(i)>10,000 nM for hDAT). In addition, AFE displays negligible binding affinities for other serotonin and dopamine receptors, indicating an excellent binding selectivity in vitro. Biodistribution studies in rats indicated that [(11)C]AFE enters the brain readily and localizes in regions known to contain high concentrations of SERT, such as the thalamus, hypothalamus, frontal cortex and striatum. Moreover, such binding in SERT-rich brain regions is reduced significantly by pretreatment with either citalopram or the cold compound itself, but not by nisoxetine or GBR 12935, thus demonstrating that [(11)C]AFE binding in the rat brain is saturable, specific and selective for the SERT. Imaging experiments in baboons indicated that the uptake pattern of [(11)C]AFE is consistent with the known distribution of SERT in the baboon brain, with high levels of radioactivity detected in the midbrain and thalamus, moderate levels in the hippocampus and striatum and low levels in the cortical regions. The uptake kinetics of [(11)C]AFE in the baboon brain is rapid, with activity in the midbrain and thalamus peaking at 15-40 min postinjection. Pretreatment of the baboon with citalopram (4 mg/kg) 20 min before radioactivity injection reduced the binding of [(11)C]AFE in all SERT-containing brain regions to the level in the cerebellum. Kinetic analysis revealed that in all brain regions examined, [(11)C]AFE specific-to-nonspecific partition coefficients (V(3)'') are similar to those of [(11)C]McN5652 and [(11)C]2-[2-[[(dimethylamino)methyl]phenyl]thio]-5-fluorophenylamine ([(11)C]AFA), but lower than those of [(11)C]2-[2-[[(dimethylamino)methyl]phenyl]thio]-5-fluoromethylphenylamine ([(11)C]AFM) or [(11)C]DASB. In summary, [(11)C]AFE appears to be a PET radioligand with fast brain uptake kinetics and can be used for the visualization and quantification of SERT in vivo.