Altanserin

Human brain mapping studies with altanserin

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-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, and another type of study have observed strong immunoreaction against 5-HT2A 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-HT2A 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-HT2A 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".

Synthesis

The reaction of 4-(4-fluorobenzoyl)piperidine [56346-57-7] (1) with 2-bromoethylamine [107-09-5] gives [1-(2-aminoethyl)piperidin-4-yl]-(4-fluorophenyl)methanone [83763-22-8] (2). The reaction of the terminal amino group with thiophosgene [463-71-8] leads to the corresponding isothiocyanate derivative, 4-fluorophenyl 1-(2-isothiocyanatoethyl)piperidin-4-yl ketone [84946-22-5] (3). Upon reaction of this reactive intermediate with ethyl anthranilate [87-25-2] (4), the transient addition product might be expected to be initially formed (**5''''). An intramolecular lactamization to the heterocyclic ring then occurs giving altanserin (**6''').

References

References

1. (December 1991). "Fluorine-18-altanserin: a radioligand for the study of serotonin receptors with PET: radiolabeling and in vivo biologic behavior in rats". Journal of Nuclear Medicine.
2. (May 1997). "In vivo binding of [18F]altanserin to rat brain 5HT2 receptors: a film and electronic autoradiographic study". Nuclear Medicine and Biology.
3. (December 2005). "Binding characteristics of the 5-HT2A receptor antagonists altanserin and MDL 100907". Synapse.
4. (February 2003). "Decreased 5-HT2a receptor binding in patients with anorexia nervosa". Journal of Nuclear Medicine.
5. (1999). "Rapid synthesis of F-18 and H-2 dual-labeled altanserin, a metabolically resistant PET ligand for 5-HT2a receptors". Journal of Labelled Compounds and Radiopharmaceuticals.
6. (September 1994). "Multicompartmental study of fluorine-18 altanserin binding to brain 5HT2 receptors in humans using positron emission tomography". European Journal of Nuclear Medicine.
7. (September 1995). "Serotonin 5HT2 receptor imaging in the human brain using positron emission tomography and a new radioligand, [18F]altanserin: results in young normal controls". Journal of Cerebral Blood Flow and Metabolism.
8. (December 1998). "Test-retest variability of serotonin 5-HT2A receptor binding measured with positron emission tomography and [18F]altanserin in the human brain". Synapse.
9. (June 2007). "Reproducibility of 5-HT2A receptor measurements and sample size estimations with [18F]altanserin PET using a bolus/infusion approach". European Journal of Nuclear Medicine and Molecular Imaging.
10. (February 2000). "PET quantification of 5-HT2A receptors in the human brain: a constant infusion paradigm with [18F]altanserin". Journal of Nuclear Medicine.
11. (August 2003). "Quantification of 5-HT2A receptors in the human brain using [18F]altanserin-PET and the bolus/infusion approach". Journal of Cerebral Blood Flow and Metabolism.
12. (November 2001). "Expression of serotonin 5-HT(2A) receptors in the human cerebellum and alterations in schizophrenia". Synapse.
13. (August 1998). "Serotonin2A receptor-like immunoreactivity in rat cerebellar Purkinje cells". Neuroscience Letters.
14. (October 1984). "Serotonin-2 binding sites in human frontal cortex and hippocampus. Selective loss of S-2A sites with age". Brain Research.
15. (December 1984). "Effects of age on dopamine and serotonin receptors measured by positron tomography in the living human brain". Science.
16. (June 2004). "Altered 5-HT(2A) receptor binding after recovery from bulimia-type anorexia nervosa: relationships to harm avoidance and drive for thinness". Neuropsychopharmacology.
17. (October 2000). "Imaging serotonergic neurotransmission in depression: hippocampal pathophysiology may mirror global brain alterations". Biological Psychiatry.
18. (April 2008). "The 5-HT2A receptor binding pattern in the human brain is strongly genetically determined". NeuroImage.
19. (February 1996). "Sex difference in 5HT2 receptor in the living human brain". Neuroscience Letters.
20. (May 2009). "Brain serotonin 2A receptor binding: relations to body mass index, tobacco and alcohol use". NeuroImage.
21. (March 2008). "Frontolimbic serotonin 2A receptor binding in healthy subjects is associated with personality risk factors for affective disorder". Biological Psychiatry.
22. (April 2007). "Cerebral 5-HT2A receptor binding is increased in patients with Tourette's syndrome". The International Journal of Neuropsychopharmacology.
23. (September 2005). "Patients with obsessive-compulsive disorder have increased 5-HT2A receptor binding in the caudate nuclei". The International Journal of Neuropsychopharmacology.
24. (November 1997). "Serotonin 5-HT2 receptor imaging in major depression: focal changes in orbito-insular cortex". The British Journal of Psychiatry.
25. (February 2004). "Decreased hippocampal 5-HT2A receptor binding in major depressive disorder: in vivo measurement with [18F]altanserin positron emission tomography". Biological Psychiatry.
26. (December 2004). "Decreased hippocampal 5-HT(2A) receptor binding in older depressed patients using [18F]altanserin positron emission tomography". Neuropsychopharmacology.
27. (September 2007). "5HT2A receptor binding is increased in borderline personality disorder". Biological Psychiatry.
28. (September 2008). "Cortical and subcortical 5-HT2A receptor binding in neuroleptic-naive first-episode schizophrenic patients". Neuropsychopharmacology.
29. (January 2008). "5-HT2A receptor density is decreased in the at-risk mental state". Psychopharmacology.
30. (December 2005). "Decreased prefrontal 5-HT2A receptor binding in subjects at enhanced risk for schizophrenia". Anatomy and Embryology.
31. (November 1996). "Visualisation of loss of 5-HT2A receptors with age in healthy volunteers using [18F]altanserin and positron emission tomographic imaging". Psychiatry Research.
32. (November 1998). "Reduced binding of [18F]altanserin to serotonin type 2A receptors in aging: persistence of effect after partial volume correction". Brain Research.
33. (March 2004). "A database of [(18)F]-altanserin binding to 5-HT(2A) receptors in normal volunteers: normative data and relationship to physiological and demographic variables". NeuroImage.
34. (December 2008). "Reduced 5-HT2A receptor binding in patients with mild cognitive impairment". Neurobiology of Aging.
35. (December 1999). "PET imaging of serotonin type 2A receptors in late-life neuropsychiatric disorders". The American Journal of Psychiatry.
36. EP0013612 idem Jan Vandenberk, Ludo Kennis, Marcel Van der Aa, Albert Van Heertum, {{US patent. 4522945 (1985 to Janssen Pharmaceutica N.V.).
37. (November 2009). "Time-efficient and convenient synthesis of [(18)F]altanserin for human PET imaging by a new work-up procedure". Applied Radiation and Isotopes.
38. (March 1998). "Automatic Synthesis of [(18)F]Altanserin, a Radiopharmaceutical for Positron Emission Tomographic Studies of the Serotonergic Type-2 Receptors". Clinical Positron Imaging.