[11C]2-(2-(Dimethylaminomethyl)phenylthio)-5-fluoromethylphenylamine

Excerpt

The neurotransmitter serotonin (5-HT) plays a major role in a variety of brain functions such as appetite, sleep, and mood. Neuropsychiatric disorders, including major depression, schizophrenia, and Alzheimer’s and Parkinson’s diseases (1-3), involve a dysfunction of the brain’s serotonin system. The serotonergic neurons – present in wide areas of the brain, including the hypothalamus, thalamus, and cerebral cortex – bear a protein called “serotonin transporter” (SERT) (4).

The SERT, located on the cell bodies and terminals of 5-HT neurons, is a specific marker for the number and integrity of presynaptic terminals of serotonin-producing neurons. It regulates neurotransmission by removing released serotonin from the extracellular space back into the presynaptic neuron. Commonly prescribed antidepressants are selective serotonin reuptake inhibitors (SSRIs), and their effects are obtained through interaction with (and inhibition of) the SERT (5). For that reason, in vivo imaging of the regional brain distribution of the SERT is an important tool to study the 5-HT system and the treatment of neuropsychiatric disorders.

A variety of in vivo radioligands for positron emission tomography (PET) have been evaluated for imaging the SERT. [¹¹C]McN5652 was the first successful and widely used agent (6, 7). However, it does have some limitations; for example, its kinetics in the brain are slow and its binding ratios in humans show low or nonspecificity. It is adequate for regions with high SERT density but often provides insufficient signal-to-noise differentials for imaging brain regions with intermediate to low SERT densities (e.g., limbic and neocortical regions) because of its high nonspecific binding.

Over recent years, new PET radioligands have been synthesized and evaluated as SERT imaging agents and alternatives to [¹¹C]McN5652. Among them, ¹¹C-labeled N,N-dimethyl-2-(2-amino-4-cyanophenylthio)benzylamine ([¹¹C]DASB), 2-(2-(dimethylaminomethyl)phenylthio)-5-fluoromethylphenylamine ([¹¹C]AFM), 5-bromo-2-[2-(dimethylaminomethylphenylthio)]phenylamine ([¹¹C]DAPA), 2-[2-(dimethylaminomethylphenylthio)]-5-iodophenylamine ([¹¹C]ADAM), and N,N-dimethyl-2-(2´-amino-4´-hydroxymethylphenylthio)benzylamine ([¹¹C]HOMADAM) (8) are based on a diaryl sulfide motif (4). [¹¹C]AFM has shown high binding affinity and good selectivity for the SERT, and displays signal/noise ratios that may enable more reliable mapping of brain regions with a low density of SERT.