Altanserin Explained

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] [<sup>18</sup>F]-setoperone can also be used in PET.

An alternative SPECT radioligand is the [<sup>123</sup>I]-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

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.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
GenderHigher binding in men[19]
Body mass indexCorrelation in cortex[20]
Neuroticism (NEO PI-R) Increase in frontolimbic region [21]
Increase [22]
[23]
(Recovered) bulimia-type anorexia nervosaDecrease in left subgenual cingulate, left parietal cortex and right occipital cortex
Unipolar depressionDecrease in a region in right hemisphere (posterolateral orbitofrontal cortex and the anterior insular cortex)[24]
Major depressive disorderDecrease in hippocampus[25]
Older depressed patientsDecrease in hippocampus[26]
Increase in hippocampus[27]
SchizophreniaNo significant cortical difference, higher binding in caudate[28]
At-risk mental stateDecrease[29] See also [30]
Decrease [31]
AgeDecrease[32]
AgeDecrease in cortical regions (except occipital), increase in cerebellum[33]
Mild cognitive impairmentDecrease[34]
Alzheimer's diseaseDecrease in amygdalo-hippocampal complex and cortical regions, such as anterior cingulate, lateral temporal cortex, prefrontal cortex and sensorimotor cortex[35]

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).

See also

Notes and References

  1. Lemaire C, Cantineau R, Guillaume M, Plenevaux A, Christiaens L . 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 . December 1991 . 1744713 .
  2. Biver F, Lotstra F, Monclus M, Dethy S, Damhaut P, Wikler D, Luxen A, Goldman S . 6 . 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 . May 1997 . 9257335 . 10.1016/s0969-8051(97)00054-1 . 2268/144404 . free .
  3. Kristiansen H, Elfving B, Plenge P, Pinborg LH, Gillings N, Knudsen GM . Binding characteristics of the 5-HT2A receptor antagonists altanserin and MDL 100907 . Synapse . 58 . 4 . 249–257 . December 2005 . 16206185 . 10.1002/syn.20205 . 19110277 .
  4. Audenaert K, Van Laere K, Dumont F, Vervaet M, Goethals I, Slegers G, Mertens J, van Heeringen C, Dierckx RA . 6 . Decreased 5-HT2a receptor binding in patients with anorexia nervosa . Journal of Nuclear Medicine . 44 . 2 . 163–169 . February 2003 . 12571204 .
  5. Tan PZ, Baldwin RM, Fu T, Charney DS, Innis RB . 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. 1999. 457–467. 0362-4803. 10.1002/(SICI)1099-1344(199905)42:5<457::AID-JLCR206>3.0.CO;2-0.
  6. Biver F, Goldman S, Luxen A, Monclus M, Forestini M, Mendlewicz J, Lotstra F . 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 . September 1994 . 7995287 . 10.1007/BF00238117 . 20200751 .
  7. Sadzot B, Lemaire C, Maquet P, Salmon E, Plenevaux A, Degueldre C, Hermanne JP, Guillaume M, Cantineau R, Comar D . 6 . 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 . 15 . 5 . 787–797 . September 1995 . 7673371 . 10.1038/jcbfm.1995.99 . 36870327 . free .
  8. Smith GS, Price JC, Lopresti BJ, Huang Y, Simpson N, Holt D, Mason NS, Meltzer CC, Sweet RA, Nichols T, Sashin D, Mathis CA . 6 . Test-retest variability of serotonin 5-HT2A receptor binding measured with positron emission tomography and [18F]altanserin in the human brain . Synapse . 30 . 4 . 380–392 . December 1998 . 9826230 . 10.1002/(SICI)1098-2396(199812)30:4<380::AID-SYN5>3.0.CO;2-U . 1297178 .
  9. Haugbøl S, Pinborg LH, Arfan HM, Frøkjaer VM, Madsen J, Dyrby TB, Svarer C, Knudsen GM . 6 . 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 . 34 . 6 . 910–915 . June 2007 . 17195073 . 10.1007/s00259-006-0296-y . 1828118 .
  10. van Dyck CH, Tan PZ, Baldwin RM, Amici LA, Garg PK, Ng CK, Soufer R, Charney DS, Innis RB . 6 . PET quantification of 5-HT2A receptors in the human brain: a constant infusion paradigm with [18F]altanserin ]. Journal of Nuclear Medicine . 41 . 2 . 234–241 . February 2000 . 10688105 . Christopher H. van Dyck .
  11. Pinborg LH, Adams KH, Svarer C, Holm S, Hasselbalch SG, Haugbøl S, Madsen J, Knudsen GM . 6 . 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 . 23 . 8 . 985–996 . August 2003 . 12902843 . 10.1097/01.WCB.0000074092.59115.23 . 6262998 . free .
  12. Eastwood SL, Burnet PW, Gittins R, Baker K, Harrison PJ . Expression of serotonin 5-HT(2A) receptors in the human cerebellum and alterations in schizophrenia . Synapse . 42 . 2 . 104–114 . November 2001 . 11574947 . 10.1002/syn.1106 . 40304220 .
  13. Maeshima T, Shutoh F, Hamada S, Senzaki K, Hamaguchi-Hamada K, Ito R, Okado N . Serotonin2A receptor-like immunoreactivity in rat cerebellar Purkinje cells . Neuroscience Letters . 252 . 1 . 72–74 . August 1998 . 9756362 . 10.1016/S0304-3940(98)00546-1 . 28549709 . Toru Maeshima .
  14. Marcusson JO, Morgan DG, Winblad B, Finch CE . Serotonin-2 binding sites in human frontal cortex and hippocampus. Selective loss of S-2A sites with age . Brain Research . 311 . 1 . 51–56 . October 1984 . 6488044 . 10.1016/0006-8993(84)91397-0 . 1203974 .
  15. Wong DF, Wagner HN, Dannals RF, Links JM, Frost JJ, Ravert HT, Wilson AA, Rosenbaum AE, Gjedde A, Douglass KH . 6 . Effects of age on dopamine and serotonin receptors measured by positron tomography in the living human brain . Science . 226 . 4681 . 1393–1396 . December 1984 . 6334363 . 10.1126/science.6334363 . 24278577 . 1984Sci...226.1393W . Albert Gjedde .
  16. Bailer UF, Price JC, Meltzer CC, Mathis CA, Frank GK, Weissfeld L, McConaha CW, Henry SE, Brooks-Achenbach S, Barbarich NC, Kaye WH . 6 . 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 . June 2004 . 15054474 . 4301578 . 10.1038/sj.npp.1300430 .
  17. Fujita M, Charney DS, Innis RB . Imaging serotonergic neurotransmission in depression: hippocampal pathophysiology may mirror global brain alterations . Biological Psychiatry . 48 . 8 . 801–812 . October 2000 . 11063976 . 10.1016/s0006-3223(00)00960-4 . 10348049 .
  18. Pinborg LH, Arfan H, Haugbol S, Kyvik KO, Hjelmborg JV, Svarer C, Frokjaer VG, Paulson OB, Holm S, Knudsen GM . 6 . The 5-HT2A receptor binding pattern in the human brain is strongly genetically determined . NeuroImage . 40 . 3 . 1175–1180 . April 2008 . 18291676 . 10.1016/j.neuroimage.2007.09.019 . 9105318 . Lars H. Pinborg .
  19. Biver F, Lotstra F, Monclus M, Wikler D, Damhaut P, Mendlewicz J, Goldman S . Sex difference in 5HT2 receptor in the living human brain . Neuroscience Letters . 204 . 1–2 . 25–28 . February 1996 . 8929969 . 10.1016/0304-3940(96)12307-7 . 43416706 .
  20. Erritzoe D, Frokjaer VG, Haugbol S, Marner L, Svarer C, Holst K, Baaré WF, Rasmussen PM, Madsen J, Paulson OB, Knudsen GM . 6 . Brain serotonin 2A receptor binding: relations to body mass index, tobacco and alcohol use . NeuroImage . 46 . 1 . 23–30 . May 2009 . 19457377 . 10.1016/j.neuroimage.2009.01.050 . Gitte Moos Knudsen . 26525667 .
  21. Frokjaer VG, Mortensen EL, Nielsen FA, Haugbol S, Pinborg LH, Adams KH, Svarer C, Hasselbalch SG, Holm S, Paulson OB, Knudsen GM . 6 . Frontolimbic serotonin 2A receptor binding in healthy subjects is associated with personality risk factors for affective disorder . Biological Psychiatry . 63 . 6 . 569–576 . March 2008 . 17884017 . 10.1016/j.biopsych.2007.07.009 . 25979780 .
  22. Haugbøl S, Pinborg LH, Regeur L, Hansen ES, Bolwig TG, Nielsen FA, Svarer C, Skovgaard LT, Knudsen GM . 6 . Cerebral 5-HT2A receptor binding is increased in patients with Tourette's syndrome . The International Journal of Neuropsychopharmacology . 10 . 2 . 245–252 . April 2007 . 16945163 . 10.1017/S1461145706006559 . vanc . free .
  23. Adams KH, Hansen ES, Pinborg LH, Hasselbalch SG, Svarer C, Holm S, Bolwig TG, Knudsen GM . 6 . Patients with obsessive-compulsive disorder have increased 5-HT2A receptor binding in the caudate nuclei . The International Journal of Neuropsychopharmacology . 8 . 3 . 391–401 . September 2005 . 15801987 . 10.1017/S1461145705005055 . free .
  24. Biver F, Wikler D, Lotstra F, Damhaut P, Goldman S, Mendlewicz J . Serotonin 5-HT2 receptor imaging in major depression: focal changes in orbito-insular cortex . The British Journal of Psychiatry . 171 . 5 . 444–448 . November 1997 . 9463603 . 10.1192/bjp.171.5.444 . 38577128 .
  25. Mintun MA, Sheline YI, Moerlein SM, Vlassenko AG, Huang Y, Snyder AZ . 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 . February 2004 . 14744461 . 10.1016/j.biopsych.2003.08.015 . 24849671 . Abraham Z. Snyder . Mark A. Mintun .
  26. Sheline YI, Mintun MA, Barch DM, Wilkins C, Snyder AZ, Moerlein SM . Decreased hippocampal 5-HT(2A) receptor binding in older depressed patients using [18F]altanserin positron emission tomography . Neuropsychopharmacology . 29 . 12 . 2235–2241 . December 2004 . 15367923 . 10.1038/sj.npp.1300555 . 1727523 . free .
  27. Soloff PH, Price JC, Meltzer CC, Fabio A, Frank GK, Kaye WH . 5HT2A receptor binding is increased in borderline personality disorder . Biological Psychiatry . 62 . 6 . 580–587 . September 2007 . 17448449 . 10.1016/j.biopsych.2006.10.022 . 12109806 .
  28. Erritzoe D, Rasmussen H, Kristiansen KT, Frokjaer VG, Haugbol S, Pinborg L, Baaré W, Svarer C, Madsen J, Lublin H, Knudsen GM, Glenthoj BY . 6 . Cortical and subcortical 5-HT2A receptor binding in neuroleptic-naive first-episode schizophrenic patients . Neuropsychopharmacology . 33 . 10 . 2435–2441 . September 2008 . 18288096 . 10.1038/sj.npp.1301656 . 7596368 . free . Electronic publication ahead of print
  29. Hurlemann R, Matusch A, Kuhn KU, Berning J, Elmenhorst D, Winz O, Kolsch H, Zilles K, Wagner M, Maier W, Bauer A . 6 . 5-HT2A receptor density is decreased in the at-risk mental state . Psychopharmacology . 195 . 4 . 579–590 . January 2008 . 17899021 . 10.1007/s00213-007-0921-x . 7784253 . Karl Zilles .
  30. Hurlemann R, Boy C, Meyer PT, Scherk H, Wagner M, Herzog H, Coenen HH, Vogeley K, Falkai P, Zilles K, Maier W, Bauer A . 6 . Decreased prefrontal 5-HT2A receptor binding in subjects at enhanced risk for schizophrenia . Anatomy and Embryology . 210 . 5–6 . 519–523 . December 2005 . 16187138 . 10.1007/s00429-005-0036-2 . Karl Zilles . 4113675 .
  31. Rosier A, Dupont P, Peuskens J, Bormans G, Vandenberghe R, Maes M, de Groot T, Schiepers C, Verbruggen A, Mortelmans L . 6 . 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 . November 1996 . 9027929 . 10.1016/S0925-4927(96)02806-5 . 32317795 .
  32. Meltzer CC, Smith G, Price JC, Reynolds CF, Mathis CA, Greer P, Lopresti B, Mintun MA, Pollock BG, Ben-Eliezer D, Cantwell MN, Kaye W, DeKosky ST . 6 . Reduced binding of [18F]altanserin to serotonin type 2A receptors in aging: persistence of effect after partial volume correction . Brain Research . 813 . 1 . 167–171 . November 1998 . 9824691 . 10.1016/S0006-8993(98)00909-3 . Steven T. DeKosky . 21884218 . Mark A. Mintun .
  33. Adams KH, Pinborg LH, Svarer C, Hasselbalch SG, Holm S, Haugbøl S, Madsen K, Frøkjaer V, Martiny L, Paulson OB, Knudsen GM . 6 . 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 . 21 . 3 . 1105–1113 . March 2004 . 15006678 . 10.1016/j.neuroimage.2003.10.046 . 24403109 .
  34. Hasselbalch SG, Madsen K, Svarer C, Pinborg LH, Holm S, Paulson OB, Waldemar G, Knudsen GM . 6 . Reduced 5-HT2A receptor binding in patients with mild cognitive impairment . Neurobiology of Aging . 29 . 12 . 1830–1838 . December 2008 . 17544547 . 10.1016/j.neurobiolaging.2007.04.011 . 23665678 .
  35. Meltzer CC, Price JC, Mathis CA, Greer PJ, Cantwell MN, Houck PR, Mulsant BH, Ben-Eliezer D, Lopresti B, DeKosky ST, Reynolds CF . 6 . PET imaging of serotonin type 2A receptors in late-life neuropsychiatric disorders . The American Journal of Psychiatry . 156 . 12 . 1871–1878 . December 1999 . 10588399 . 10.1176/ajp.156.12.1871 . 7678215 .

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