trans-(+)-1,2,3,5,6,10b-Hexahydro-6-(4-([11C]methylthio)-phenyl)pyrrolo-(2,1-a)-isoquinoline

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, Alzheimer’s disease, and Parkinson’s disease (1-3), involve a dysfunction of the brain’s 5-HT system.

The serotonergic neurons – present in wide areas of the brain, including the raphe nuclei, 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 5-HT from the extracellular space back into the presynaptic neuron. Commonly prescribed antidepressants are selective serotonin reuptake inhibitors, 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 for studying 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. trans-(+)1,2,3,5,6,10b-Hexahydro-6-(4-([¹¹C]methylthio)-phenyl)pyrrolo-(2,1-a)-isoquinoline ([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 although adequate for regions with high SERT density, it 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 (e.g [¹¹C]DASB, [¹¹C]AFM, [¹¹C]ADAM, [¹¹C]HOMADAM).

[¹¹C]McN5652 has two optical isomeric forms. The ability of its geometric trans (+), pharmacologically active enantiomer, [¹¹C](+)McN5652, to block the SERT is at least two orders of magnitude higher than that of its inactive enantiomer, [¹¹C](-)McN5652 (8, 9) (inhibition constant (K_i) ~ 0.7 nM for [¹¹C](+)McN5652 versus 0.4 nM for [¹¹C](-)McN5652) (also see the In Vitro Studies section). Brain uptake and retention of [¹¹C](+)McN5652 correspond to the distribution of the SERT in rodents, non-human primates, and humans. Several methods have been used to quantify [¹¹C](+)McN5652-specific binding, but the high level of nonspecific binding, the differences in nonspecific binding among regions, and the slow equilibration between specific and nonspecific binding populations have made such a quantification difficult (10).