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Altanserin

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Altanserin
Clinical data
ATC code
  • none
Identifiers
  • 3-[2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl]-2-sulfanylidene-1H-quinazolin-4-one
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.071.272 Edit this at Wikidata
Chemical and physical data
FormulaC22H22FN3O2S
Molar mass411.50 g·mol−1
3D model (JSmol)
  • Fc1ccc(cc1)C(=O)C4CCN(CCN3C(=O)c2ccccc2NC3=S)CC4
  • 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) checkY
  • Key:SMYALUSCZJXWHG-UHFFFAOYSA-N checkY
  (verify)

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.[1][2]

An alternative for PET imaging the 5-HT2A receptor is the [11C]volinanserin (MDL-100,907) radioligand. 18F-altanserin and 3H-volinanserin have shown very comparable binding.[3] Both altanserin and MDL 100,907 are 5-HT2A receptor antagonists.[3] [18F]-setoperone can also be used in PET.

An alternative SPECT radioligand is the [123I]-5-I-R91150 receptor antagonist.[4]

A rapid chemical synthesis of fluorine-18 and H-2 dual-labeled altanserin has been described.[5]

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

[edit]
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.[6][7] Some of these studies have considered methodogical issues such as the reproducibility of the method[8][9] or whether to use constant infusion[10] or bolus-infusion[11] 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,[12] and another type of study have observed strong immunoreaction against 5-HT2A receptor protein in rat Purkinje cells.[13]

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

The result for recovered bulimia-type anorexia nervosa[16] is in line with a SPECT study of anorexia nervosa patients, that found a decrease in frontal, occipital and parietal cortices.[4] The results of PET studies of the 5-HT2A in depression has been mixed.[17]

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".[18]

Altanserin neuroimaging studies
What Result Reference
Gender Higher binding in men [19]
Body mass index Correlation in cortex [20]
Neuroticism (NEO PI-R) Increase in frontolimbic region [21]
Tourette syndrome Increase [22]
Obsessive-compulsive disorder Increase in caudate nuclei [23]
(Recovered) bulimia-type anorexia nervosa Decrease in left subgenual cingulate, left parietal cortex and right occipital cortex [16]
Unipolar depression Decrease in a region in right hemisphere (posterolateral orbitofrontal cortex and the anterior insular cortex) [24]
Major depressive disorder Decrease in hippocampus [25]
Older depressed patients Decrease in hippocampus [26]
Borderline personality disorder Increase in hippocampus [27]
Schizophrenia No significant cortical difference, higher binding in caudate [28]
At-risk mental state Decrease [29] See also [30]
Age Decrease [31]
Age Decrease [32]
Age Decrease in cortical regions (except occipital), increase in cerebellum [33]
Mild cognitive impairment Decrease [34]
Alzheimer's disease Decrease in amygdalo-hippocampal complex and cortical regions, such as anterior cingulate, lateral temporal cortex, prefrontal cortex and sensorimotor cortex [35]

Synthesis

[edit]
Patent:[36] Radiolabelled:[37][38][5]

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).

See also

[edit]

References

[edit]
  1. ^ Lemaire C, Cantineau R, Guillaume M, Plenevaux A, Christiaens L (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. 32 (12): 2266–2272. PMID 1744713.
  2. ^ Biver F, Lotstra F, Monclus M, Dethy S, Damhaut P, Wikler D, et al. (May 1997). "In vivo binding of [18F]altanserin to rat brain 5HT2 receptors: a film and electronic autoradiographic study". Nuclear Medicine and Biology. 24 (4): 357–360. doi:10.1016/s0969-8051(97)00054-1. hdl:2268/144404. PMID 9257335.
  3. ^ a b Kristiansen H, Elfving B, Plenge P, Pinborg LH, Gillings N, Knudsen GM (December 2005). "Binding characteristics of the 5-HT2A receptor antagonists altanserin and MDL 100907". Synapse. 58 (4): 249–257. doi:10.1002/syn.20205. PMID 16206185. S2CID 19110277.
  4. ^ a b Audenaert K, Van Laere K, Dumont F, Vervaet M, Goethals I, Slegers G, et al. (February 2003). "Decreased 5-HT2a receptor binding in patients with anorexia nervosa". Journal of Nuclear Medicine. 44 (2): 163–169. PMID 12571204.
  5. ^ a b Tan PZ, Baldwin RM, Fu T, Charney DS, Innis RB (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. 42 (5): 457–467. doi:10.1002/(SICI)1099-1344(199905)42:5<457::AID-JLCR206>3.0.CO;2-0. ISSN 0362-4803.
  6. ^ Biver F, Goldman S, Luxen A, Monclus M, Forestini M, Mendlewicz J, Lotstra F (September 1994). "Multicompartmental study of fluorine-18 altanserin binding to brain 5HT2 receptors in humans using positron emission tomography". European Journal of Nuclear Medicine. 21 (9): 937–946. doi:10.1007/BF00238117. PMID 7995287. S2CID 20200751.
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  13. ^ Maeshima T, Shutoh F, Hamada S, Senzaki K, Hamaguchi-Hamada K, Ito R, Okado N (August 1998). "Serotonin2A receptor-like immunoreactivity in rat cerebellar Purkinje cells". Neuroscience Letters. 252 (1): 72–74. doi:10.1016/S0304-3940(98)00546-1. PMID 9756362. S2CID 28549709.
  14. ^ Marcusson JO, Morgan DG, Winblad B, Finch CE (October 1984). "Serotonin-2 binding sites in human frontal cortex and hippocampus. Selective loss of S-2A sites with age". Brain Research. 311 (1): 51–56. doi:10.1016/0006-8993(84)91397-0. PMID 6488044. S2CID 1203974.
  15. ^ Wong DF, Wagner HN, Dannals RF, Links JM, Frost JJ, Ravert HT, et al. (December 1984). "Effects of age on dopamine and serotonin receptors measured by positron tomography in the living human brain". Science. 226 (4681): 1393–1396. Bibcode:1984Sci...226.1393W. doi:10.1126/science.6334363. PMID 6334363. S2CID 24278577.
  16. ^ a b Bailer UF, Price JC, Meltzer CC, Mathis CA, Frank GK, Weissfeld L, et al. (June 2004). "Altered 5-HT(2A) receptor binding after recovery from bulimia-type anorexia nervosa: relationships to harm avoidance and drive for thinness". Neuropsychopharmacology. 29 (6): 1143–1155. doi:10.1038/sj.npp.1300430. PMC 4301578. PMID 15054474.
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  18. ^ Pinborg LH, Arfan H, Haugbol S, Kyvik KO, Hjelmborg JV, Svarer C, et al. (April 2008). "The 5-HT2A receptor binding pattern in the human brain is strongly genetically determined". NeuroImage. 40 (3): 1175–1180. doi:10.1016/j.neuroimage.2007.09.019. PMID 18291676. S2CID 9105318.
  19. ^ Biver F, Lotstra F, Monclus M, Wikler D, Damhaut P, Mendlewicz J, Goldman S (February 1996). "Sex difference in 5HT2 receptor in the living human brain". Neuroscience Letters. 204 (1–2): 25–28. doi:10.1016/0304-3940(96)12307-7. PMID 8929969. S2CID 43416706.
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  25. ^ Mintun MA, Sheline YI, Moerlein SM, Vlassenko AG, Huang Y, Snyder AZ (February 2004). "Decreased hippocampal 5-HT2A receptor binding in major depressive disorder: in vivo measurement with [18F]altanserin positron emission tomography". Biological Psychiatry. 55 (3): 217–224. doi:10.1016/j.biopsych.2003.08.015. PMID 14744461. S2CID 24849671.
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  31. ^ Rosier A, Dupont P, Peuskens J, Bormans G, Vandenberghe R, Maes M, et al. (November 1996). "Visualisation of loss of 5-HT2A receptors with age in healthy volunteers using [18F]altanserin and positron emission tomographic imaging". Psychiatry Research. 68 (1): 11–22. doi:10.1016/S0925-4927(96)02806-5. PMID 9027929. S2CID 32317795.
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  36. ^ EP0013612 idem Jan Vandenberk, Ludo Kennis, Marcel Van der Aa, Albert Van Heertum, U.S. patent 4,522,945 (1985 to Janssen Pharmaceutica N.V.).
  37. ^ Massarweh G, Kovacevic M, Rosa-Neto P, Evans AC, Diksic M, Schirrmacher R (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. 67 (11): 2040–2043. doi:10.1016/j.apradiso.2009.07.020. PMID 19692252.
  38. ^ Monclus M, Van Naemen J, Mulleneers E, Damhaut P, Luxen A, Goldman S (March 1998). "Automatic Synthesis of [(18)F]Altanserin, a Radiopharmaceutical for Positron Emission Tomographic Studies of the Serotonergic Type-2 Receptors". Clinical Positron Imaging. 1 (2): 111–116. doi:10.1016/s1095-0397(98)00005-3. hdl:2268/144402. PMID 14516599.