Altanserin

Altanserin

Systematic (IUPAC) name
3-[2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl]-2-sulfanylidene-1H-quinazolin-4-one
Identifiers
CAS Number	76330-71-7 Y
ATC code	none
PubChem	CID: 3033677
ChemSpider	2298299 Y
UNII	5015H744JQ Y
ChEMBL	CHEMBL62919 Y
Chemical data
Formula	C22H22FN3O2S
Molecular mass	411.49 g/mol
SMILES Fc1ccc(cc1)C(=O)C4CCN(CCN3C(=O)c2ccccc2NC3=S)CC4
InChI InChI=1S/C22H22FN3O2S/c23-17-7-5-15(6-8-17)20(27)16-9-11-25(12-10-16)13-14-26-21(28)18-3-1-2-4-19(18)24-22(26)29/h1-8,16H,9-14H2,(H,24,29) Y Key:SMYALUSCZJXWHG-UHFFFAOYSA-N Y
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Altanserin is a compound that binds to the 5-HT_2A receptor (5-Hydroxytryptamine (serotonin) 2A receptor). Labeled with the isotope fluorine-18 it is used as a radioligand in positron emission tomography (PET) studies of the brain, i.e., studies of the 5-HT_2A neuroreceptors. Besides human neuroimaging studies altanserin has also been used in the study of rats.

An alternative for PET imaging the 5-HT_2A receptor is the [¹¹C]MDL 100,907 radioligand. Fluorine-18-altanserin and tritium-MDL 100,907 have shown very comparable binding. Both altanserin and MDL 100,907 are 5-HT_2A receptor antagonists. [¹⁸F]-setoperone can also be used in PET.

An alternative SPECT radioligand is the [¹²³I]-5-I-R91150 receptor antagonist.

A rapid chemical synthesis of fluorine-18 and H-2 dual-labeled altanserin has been described.

Other ligands for other parts of the serotonin system used in PET studies are, e.g., DASB, ketanserin and WAY-100635.

Human brain mapping studies with altanserin

A PET scanner. Human experiments with fluorine-18 altanserin are performed in these types of brain scanners.

As of 2007 altanserin is probably not used in clinical routine. However, there have been performed several research-based neuroimaging studies with the compound in humans since the 1990s. Some of these studies have considered methodogical issues such as the reproducibility of the method or whether to use constant infusion or bolus-infusion delivery of altanserin. Other studies have compared altanserin binding to subject variables such as age, personality trait and neuropsychiatric disorder.

The altanserin PET scan shows high binding in neocortex. The cerebellum is often regarded as a region with no specific 5-HT_2A binding and the brain region is used as a reference in some studies, even though an autoradiography study has found nonnegligible levels of 5-HT_2A binding in the human cerebellum, and another type of study have observed strong immunoreaction against 5-HT_2A receptor protein in rat Purkinje cells.

In the table below is an overview of the results of altanserin binding seen in human PET-studies. A consistent finding across altanserin studies has been that the binding decreases with age. This is in line with in vitro studies of the 5-HT_2A receptor, as well as PET studies with other radioligands that binds to the receptor.

The result for recovered bulimia-type anorexia nervosa is in line with a SPECT study of anorexia nervosa patients, that found a decrease in frontal, occipital and parietal cortices. The results of PET studies of the 5-HT_2A in depression has been mixed.

Altanserin binding has also been examine in twins, where one study showed higher correlation between monozygotic twin pairs than between dizygotic twin pairs, giving evidence that the binding is "strongly genetically determined".

Altanserin neuroimaging studies

What	Result	Reference
Gender	Higher binding in men
Body mass index	Correlation in cortex
Neuroticism (NEO PI-R)	Increase in frontolimbic region
Tourette syndrome	Increase
Obsessive-compulsive disorder	Increase in caudate nuclei
(Recovered) bulimia-type anorexia nervosa	Decrease in left subgenual cingulate, left parietal cortex and right occipital cortex
Unipolar depression	Decrease in a region in right hemisphere (posterolateral orbitofrontal cortex and the anterior insular cortex)
Major depressive disorder	Decrease in hippocampus
Older depressed patients	Decrease in hippocampus
Borderline personality disorder	Increase in hippocampus
Schizophrenia	No significant cortical difference, higher binding in caudate
At-risk mental state	Decrease	See also
Age	Decrease
Age	Decrease
Age	Decrease in cortical regions (except occipital), increase in cerebellum
Mild cognitive impairment	Decrease
Alzheimer's disease	Decrease in amygdalo-hippocampal complex and cortical regions, such as anterior cingulate, lateral temporal cortex, prefrontal cortex and sensorimotor cortex

Synthesis

Condensation of ethyl anthranilates with isothiocyanates provides entry to a closely related compound in which the carbonyl at the 2 position is replaced by a thione.

Altanserin synthesis: U.S. Patent 4,522,945

The sequence starts with the alkylation of pyrrolidine nitrogen in (1) with 2-bromoethylamine. Reaction of the primary amine in the product (2) with thiophosgene leads to the isothiocyanate derivative (3). Reaction of that reactive intermediate with methyl anthranilate (4) leads initially to the transient addition product (5). This then undergoes the customary internal ester exchange reaction to form the heterocyclic ring. There is thus obtained the serotonin antagonist altanserin (6).