Altanserin
{{Short description|Chemical compound}}
{{Drugbox
| Watchedfields = changed
| verifiedrevid = 438043109
| IUPAC_name = 3-[2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl]-2-sulfanylidene-1H-quinazolin-4-one
| image = Altanserin.svg
| image_class = skin-invert-image
| tradename =
| pregnancy_category =
| legal_status =
| routes_of_administration =
| bioavailability =
| protein_bound =
| metabolism =
| elimination_half-life =
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| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 76330-71-7
| ATC_prefix = none
| ATC_suffix =
| PubChem = 3033677
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank =
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 2298299
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 5015H744JQ
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 62919
| C=22 | H=22 | F=1 | N=3 | O=2 | S=1
| SMILES = Fc1ccc(cc1)C(=O)C4CCN(CCN3C(=O)c2ccccc2NC3=S)CC4
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 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)
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = SMYALUSCZJXWHG-UHFFFAOYSA-N
}}
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.{{cite journal | vauthors = Lemaire C, Cantineau R, Guillaume M, Plenevaux A, Christiaens L | title = Fluorine-18-altanserin: a radioligand for the study of serotonin receptors with PET: radiolabeling and in vivo biologic behavior in rats | journal = Journal of Nuclear Medicine | volume = 32 | issue = 12 | pages = 2266–2272 | date = December 1991 | pmid = 1744713 }}{{cite journal | vauthors = Biver F, Lotstra F, Monclus M, Dethy S, Damhaut P, Wikler D, Luxen A, Goldman S | display-authors = 6 | title = In vivo binding of [18F]altanserin to rat brain 5HT2 receptors: a film and electronic autoradiographic study | journal = Nuclear Medicine and Biology | volume = 24 | issue = 4 | pages = 357–360 | date = May 1997 | pmid = 9257335 | doi = 10.1016/s0969-8051(97)00054-1 | hdl = 2268/144404 | hdl-access = free }}
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.{{cite journal | vauthors = Kristiansen H, Elfving B, Plenge P, Pinborg LH, Gillings N, Knudsen GM | title = Binding characteristics of the 5-HT2A receptor antagonists altanserin and MDL 100907 | journal = Synapse | volume = 58 | issue = 4 | pages = 249–257 | date = December 2005 | pmid = 16206185 | doi = 10.1002/syn.20205 | s2cid = 19110277 }}
Both altanserin and MDL 100,907 are 5-HT2A receptor antagonists.
[18F]-setoperone can also be used in PET.
An alternative SPECT radioligand is the [123I]-5-I-R91150 receptor antagonist.{{cite journal | vauthors = Audenaert K, Van Laere K, Dumont F, Vervaet M, Goethals I, Slegers G, Mertens J, van Heeringen C, Dierckx RA | display-authors = 6 | title = Decreased 5-HT2a receptor binding in patients with anorexia nervosa | journal = Journal of Nuclear Medicine | volume = 44 | issue = 2 | pages = 163–169 | date = February 2003 | pmid = 12571204 }}
A rapid chemical synthesis of fluorine-18 and H-2 dual-labeled altanserin has been described.{{cite journal| vauthors = Tan PZ, Baldwin RM, Fu T, Charney DS, Innis RB |title=Rapid synthesis of F-18 and H-2 dual-labeled altanserin, a metabolically resistant PET ligand for 5-HT2a receptors|journal=Journal of Labelled Compounds and Radiopharmaceuticals|volume=42|issue=5|year=1999|pages=457–467|issn=0362-4803|doi=10.1002/(SICI)1099-1344(199905)42:5<457::AID-JLCR206>3.0.CO;2-0}}
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
Image:ECAT-Exact-HR--PET-Scanner.jpg. 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.{{cite journal | vauthors = Biver F, Goldman S, Luxen A, Monclus M, Forestini M, Mendlewicz J, Lotstra F | title = Multicompartmental study of fluorine-18 altanserin binding to brain 5HT2 receptors in humans using positron emission tomography | journal = European Journal of Nuclear Medicine | volume = 21 | issue = 9 | pages = 937–946 | date = September 1994 | pmid = 7995287 | doi = 10.1007/BF00238117 | s2cid = 20200751 }}{{cite journal | vauthors = Sadzot B, Lemaire C, Maquet P, Salmon E, Plenevaux A, Degueldre C, Hermanne JP, Guillaume M, Cantineau R, Comar D | display-authors = 6 | title = Serotonin 5HT2 receptor imaging in the human brain using positron emission tomography and a new radioligand, [18F]altanserin: results in young normal controls | journal = Journal of Cerebral Blood Flow and Metabolism | volume = 15 | issue = 5 | pages = 787–797 | date = September 1995 | pmid = 7673371 | doi = 10.1038/jcbfm.1995.99 | s2cid = 36870327 | doi-access = free }}
Some of these studies have considered methodogical issues such as the reproducibility of the method{{cite journal | vauthors = Smith GS, Price JC, Lopresti BJ, Huang Y, Simpson N, Holt D, Mason NS, Meltzer CC, Sweet RA, Nichols T, Sashin D, Mathis CA | display-authors = 6 | title = Test-retest variability of serotonin 5-HT2A receptor binding measured with positron emission tomography and [18F]altanserin in the human brain | journal = Synapse | volume = 30 | issue = 4 | pages = 380–392 | date = December 1998 | pmid = 9826230 | doi = 10.1002/(SICI)1098-2396(199812)30:4<380::AID-SYN5>3.0.CO;2-U | s2cid = 1297178 }}{{cite journal | vauthors = Haugbøl S, Pinborg LH, Arfan HM, Frøkjaer VM, Madsen J, Dyrby TB, Svarer C, Knudsen GM | display-authors = 6 | title = Reproducibility of 5-HT2A receptor measurements and sample size estimations with [18F]altanserin PET using a bolus/infusion approach | journal = European Journal of Nuclear Medicine and Molecular Imaging | volume = 34 | issue = 6 | pages = 910–915 | date = June 2007 | pmid = 17195073 | doi = 10.1007/s00259-006-0296-y | s2cid = 1828118 }}
or whether to use constant infusion{{cite journal | vauthors = van Dyck CH, Tan PZ, Baldwin RM, Amici LA, Garg PK, Ng CK, Soufer R, Charney DS, Innis RB | display-authors = 6 | title = PET quantification of 5-HT2A receptors in the human brain: a constant infusion paradigm with [18F]altanserin | journal = Journal of Nuclear Medicine | volume = 41 | issue = 2 | pages = 234–241 | date = February 2000 | pmid = 10688105 | url = http://jnm.snmjournals.org/cgi/content/abstract/41/2/234 | author-link1 = Christopher H. van Dyck }} or bolus-infusion{{cite journal | vauthors = Pinborg LH, Adams KH, Svarer C, Holm S, Hasselbalch SG, Haugbøl S, Madsen J, Knudsen GM | display-authors = 6 | title = Quantification of 5-HT2A receptors in the human brain using [18F]altanserin-PET and the bolus/infusion approach | journal = Journal of Cerebral Blood Flow and Metabolism | volume = 23 | issue = 8 | pages = 985–996 | date = August 2003 | pmid = 12902843 | doi = 10.1097/01.WCB.0000074092.59115.23 | s2cid = 6262998 | doi-access = free }} 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,{{cite journal | vauthors = Eastwood SL, Burnet PW, Gittins R, Baker K, Harrison PJ | title = Expression of serotonin 5-HT(2A) receptors in the human cerebellum and alterations in schizophrenia | journal = Synapse | volume = 42 | issue = 2 | pages = 104–114 | date = November 2001 | pmid = 11574947 | doi = 10.1002/syn.1106 | s2cid = 40304220 }}
and another type of study have observed strong immunoreaction against 5-HT2A receptor protein in rat Purkinje cells.{{cite journal | vauthors = Maeshima T, Shutoh F, Hamada S, Senzaki K, Hamaguchi-Hamada K, Ito R, Okado N | title = Serotonin2A receptor-like immunoreactivity in rat cerebellar Purkinje cells | journal = Neuroscience Letters | volume = 252 | issue = 1 | pages = 72–74 | date = August 1998 | pmid = 9756362 | doi = 10.1016/S0304-3940(98)00546-1 | s2cid = 28549709 | author-link1 = Toru Maeshima }}
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,{{cite journal | vauthors = Marcusson JO, Morgan DG, Winblad B, Finch CE | title = Serotonin-2 binding sites in human frontal cortex and hippocampus. Selective loss of S-2A sites with age | journal = Brain Research | volume = 311 | issue = 1 | pages = 51–56 | date = October 1984 | pmid = 6488044 | doi = 10.1016/0006-8993(84)91397-0 | s2cid = 1203974 }}
as well as PET studies with other radioligands that binds to the receptor.{{cite journal | vauthors = Wong DF, Wagner HN, Dannals RF, Links JM, Frost JJ, Ravert HT, Wilson AA, Rosenbaum AE, Gjedde A, Douglass KH | display-authors = 6 | title = Effects of age on dopamine and serotonin receptors measured by positron tomography in the living human brain | journal = Science | volume = 226 | issue = 4681 | pages = 1393–1396 | date = December 1984 | pmid = 6334363 | doi = 10.1126/science.6334363 | s2cid = 24278577 | bibcode = 1984Sci...226.1393W | author-link9 = Albert Gjedde }}
The result for recovered bulimia-type anorexia nervosa{{cite journal | vauthors = Bailer UF, Price JC, Meltzer CC, Mathis CA, Frank GK, Weissfeld L, McConaha CW, Henry SE, Brooks-Achenbach S, Barbarich NC, Kaye WH | display-authors = 6 | title = Altered 5-HT(2A) receptor binding after recovery from bulimia-type anorexia nervosa: relationships to harm avoidance and drive for thinness | journal = Neuropsychopharmacology | volume = 29 | issue = 6 | pages = 1143–1155 | date = June 2004 | pmid = 15054474 | pmc = 4301578 | doi = 10.1038/sj.npp.1300430 }}
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.{{cite journal | vauthors = Fujita M, Charney DS, Innis RB | title = Imaging serotonergic neurotransmission in depression: hippocampal pathophysiology may mirror global brain alterations | journal = Biological Psychiatry | volume = 48 | issue = 8 | pages = 801–812 | date = October 2000 | pmid = 11063976 | doi = 10.1016/s0006-3223(00)00960-4 | s2cid = 10348049 }}
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".{{cite journal | vauthors = Pinborg LH, Arfan H, Haugbol S, Kyvik KO, Hjelmborg JV, Svarer C, Frokjaer VG, Paulson OB, Holm S, Knudsen GM | display-authors = 6 | title = The 5-HT2A receptor binding pattern in the human brain is strongly genetically determined | journal = NeuroImage | volume = 40 | issue = 3 | pages = 1175–1180 | date = April 2008 | pmid = 18291676 | doi = 10.1016/j.neuroimage.2007.09.019 | s2cid = 9105318 | author-link1 = Lars H. Pinborg }}
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).