In This Issue pubs.acs.org/chemneuro
■
SIDESTEPPING SERT: NEW PATHWAYS FOR ANTIDEPRESSANTS
Here, Kim et al. (DOI: 10.1021/acschemneuro.6b00445) design and synthesize 4-(3-[18F]fluorophenethoxy)pyrimidine, a potential PET radioligand for the 5-HT2C receptor that binds with high specificity and affinity. The authors installed the 18F radiolabel via nucleophilic aromatic substitution of a diaryliodonium tosylate precursor. Next, the radioligand was administered intravenously in rats with or without the 5-HT2C receptor agonist lorcaserin. PET imaging studies showed that the ligand was successfully taken up into the brain and demonstrated selective binding to rat 5-HT2C receptors.
■
The most commonly prescribed treatments for depression are selective serotonin reuptake inhibitors (SSRIs), which block the serotonin transporter (SERT) from clearing the serotonin neurotransmitter following synaptic release. This results in elevated levels of serotonin in the extracellular domain; however, the efficacy of SSRIs is limited by delayed alleviation of symptoms, high nonresponder rates, and side effects that discourage patient use. As a result, next-generation antidepressants such as vortioxetine (Trintellix) are being developed that engage with other targets while retaining SERT inhibition activity. In this issue, Nackenoff et al. (DOI: 10.1021/acschemneuro.7b00038) probe the engagement of vortioxetine with SERT. To do so, they employed the SERT Met172 mouse model, which disrupts high-affinity interactions of antidepressants with SERT. First, the authors performed a series of experiments to ascertain that the drug indeed displayed reduced interactions with this target, validating the model system. Additionally, they found that, despite diminished binding with SERT, vortioxetine still induces antidepressant effects in the mice, which is attributed to SERTindependent target engagement.
■
Mutations in the serotonin transporter, even a single amino acid alteration such as isoleucine to methionine (known as I172M mSERT), can lead to substantially diminished affinity for antidepressants such as SSRIs. However, the interactions of antidepressant metabolites with this mutant receptor are less well-known. In this issue, Krout and co-workers (DOI: 10.1021/ acschemneuro.6b00343) evaluate the selectivity and potency of the metabolites of several common antidepressantsspecifically, the demethylated metabolites of SSRIs and SNRIs that are produced in the liver. Metabolites, such as norfluoxetine and desmethylsertraline, lose their ability to selectively inhibit SERT in mice expressing 172M mSERT; other metabolites, such as desvenlafaxine and desmethylcitalopram, are capable of inhibiting the antidepressant-insensitive 172M SERT. These results demonstrate that metabolites could play a significant role in the overall inhibition of SERT and may do so by binding to sites other than the canonical antidepressant SERT binding site. Effects of SSRI metabolites should be taken into account when determining the effectiveness of a treatment program.
A NEW PET RADIOLIGAND FOR BRAIN IMAGING
Serotonin, also known as 5-hydroxytryptamine (5-HT), is a key neurotransmitter that binds up to 14 distinct serotonin receptor proteins. Of particular interest is the 5-HT2C receptor, an excitatory 5-HT receptor distributed throughout the CNS that is associated with several diseases such as depression, schizophrenia, and anxiety. Positron emission tomography (PET) enables the noninvasive imaging of receptors, but currently no radiotracer exists for the tracking of the 5-HT2C receptor in vivo. © 2017 American Chemical Society
EFFECTS OF ANTIDEPRESSANT METABOLITES ON SEROTONIN RECEPTOR BINDING
Special Issue: Serotonin Research 2016 Published: May 17, 2017 892
DOI: 10.1021/acschemneuro.7b00161 ACS Chem. Neurosci. 2017, 8, 892−892
