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Altanserin

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Altanserin

Altanserin
Systematic (IUPAC) name
3-[2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl]-2-sulfanylidene-1H-quinazolin-4-one
Identifiers
CAS Registry Number  YesY
ATC code None
PubChem CID:
ChemSpider  YesY
UNII  YesY
ChEMBL  YesY
Chemical data
Formula C22H22FN3O2S
Molecular mass 411.49 g/mol[1]
 YesY   

Altanserin is a compound that binds to the 5-HT2A 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-HT2A neuroreceptors. Besides human neuroimaging studies altanserin has also been used in the study of rats.[2][3]

An alternative for PET imaging the 5-HT2A receptor is the [11C]MDL 100,907 radioligand. Fluorine-18-altanserin and tritium-MDL 100,907 have shown very comparable binding.[4] Both altanserin and MDL 100,907 are 5-HT2A receptor antagonists.[4] [18F]-setoperone can also be used in PET.

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

A rapid chemical synthesis of fluorine-18 and H-2 dual-labeled altanserin has been described.[6]

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.[7][8] Some of these studies have considered methodogical issues such as the reproducibility of the method[9][10] or whether to use constant infusion[11] or bolus-infusion[12] 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-HT2A binding and the brain region is used as a reference in some studies, even though an autoradiography study has found nonnegligible levels of 5-HT2A binding in the human cerebellum,[13] and another type of study have observed strong immunoreaction against 5-HT2A receptor protein in rat Purkinje cells.[14]

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-HT2A receptor,[15] as well as PET studies with other radioligands that binds to the receptor.[16]

The result for recovered bulimia-type anorexia nervosa[17] is in line with a SPECT study of anorexia nervosa patients, that found a decrease in frontal, occipital and parietal cortices.[5] The results of PET studies of the 5-HT2A in depression has been mixed.[18]

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".[19]

Altanserin neuroimaging studies
What Result Reference
Sex Higher binding in men [20]
Body mass index Correlation in cortex [21]
Neuroticism (NEO PI-R) Increase in frontolimbic region [22]
Tourette syndrome Increase [23]
Obsessive-compulsive disorder Increase in caudate nuclei [24]
(Recovered) bulimia-type anorexia nervosa Decrease in left subgenual cingulate, left parietal cortex and right occipital cortex [17]
Unipolar depression Decrease in a region in right hemisphere (posterolateral orbitofrontal cortex and the anterior insular cortex) [25]
Major depressive disorder Decrease in hippocampus [26]
Older depressed patients Decrease in hippocampus [27]
Borderline personality disorder Increase in hippocampus [28]
Schizophrenia No significant cortical difference, higher binding in caudate [29]
At-risk mental state Decrease [30] See also [31]
Age Decrease [32]
Age Decrease [33]
Age Decrease in cortical regions (except occipital), increase in cerebellum [34]
Mild cognitive impairment Decrease [35]
Alzheimer's disease Decrease in amygdalo-hippocampal complex and cortical regions, such as anterior cingulate, lateral temporal cortex, prefrontal cortex and sensorimotor cortex [36]

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).

References

  1. ^ ABX, Altanserin, Radeberg, Germany.
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  5. ^ a b
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  17. ^ a b
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  29. ^ Electronic publication ahead of print
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