DASB

DASB, also known as 3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile, is a compound that binds to the serotonin transporter. Labeled with carbon-11 — a radioactive isotope — it has been used as a radioligand in neuroimaging with positron emission tomography (PET) since around year 2000.[1] In this context it is regarded as one of the superior radioligands for PET study of the serotonin transporter in the brain,[2] since it has high selectivity for the serotonin transporter.[3]

DASB

DASB (above) and [C-11]DASB
Radioactive carbon atom marked in cyan
Identifiers
IUPAC name 3-amino-4-[2-[(di(methyl)amino)methyl]phenyl]sulfanylbenzonitrile
CAS Number	627490-01-1 11C-labelled: 296774-13-5
PubChem CID	10446567 11C-labelled: 656408
ChemSpider	8621986 11C-labelled: 570800
UNII	PP549Z0645 11C-labelled: FJU46Q2BPU
Chemical and physical data
Formula	C16H17N3S
Molar mass	283.39 g·mol^−1
3D model (JSmol)	Interactive image 11C-labelled: Interactive image
SMILES N#Cc2ccc(Sc1c(cccc1)CN(C)C)c(c2)N 11C-labelled: [11CH3]N(C)Cc1ccccc1Sc2ccc(cc2N)C#N
InChI InChI=1S/C16H17N3S/c1-19(2)11-13-5-3-4-6-15(13)20-16-8-7-12(10-17)9-14(16)18/h3-9H,11,18H2,1-2H3 Key:UVWLEPXXYOYDGR-UHFFFAOYSA-N 11C-labelled: InChI=1S/C16H17N3S/c1-19(2)11-13-5-3-4-6-15(13)20-16-8-7-12(10-17)9-14(16)18/h3-9H,11,18H2,1-2H3/i1-1 Key:UVWLEPXXYOYDGR-BJUDXGSMSA-N
(what is this?)  (verify)

The DASB image from a human PET scan shows high binding in the midbrain, thalamus and striatum, moderate binding in the medial temporal lobe and anterior cingulate, and low binding in neocortex. The cerebellum is often regarded as a region with no specific serotonin transporter binding and the brain region is used as a reference in some studies.[4]

Since the serotonin transporter is the target of SSRIs used in the treatment of major depression it has been natural to examine DASB binding in depressed patients. Several such research studies have been performed.[5]

Closely allied agents from the Diphenylsulfide family of Drugs, particularly Bipenamol, Moxifetin, 403U76, or WO 1997017325 are competent 5HT based reuptake inhibitor thymoleptic agents; these may have been overlooked. One can clearly see that this is acyclic, and that the Phenothiazine would be foreseeable at least in theory, although not on pubchem database.

There are a number of alternative PET radioligands for imaging the serotonin transporter: [¹¹C]ADAM, [¹¹C]MADAM, [¹¹C]AFM, [¹¹C]DAPA, [¹¹C]McN5652, and [¹¹C]-NS 4194. A related molecule to DASB, that can be labeled with fluorine-18, has also been suggested as a PET radioligand.[6] With single-photon emission computed tomography (SPECT) using the radioisotope iodine-123 there are further radioligands available: [¹²³I]ODAM, [¹²³I]IDAM, [¹²³I]ADAM,[7] and [¹²³I]β-CIT.[2] A few studies have examined the difference in binding between the radioligands in nonhuman primates,[8][9] as well as in pigs.[10]

Other compounds that can be labeled to work as PET radioligands for the study of the serotonin system are, e.g., altanserin and WAY-100635.

Methodological issues

The binding potential of DASB can be estimated with kinetic modeling on a series of brain scans.[11]

A test-retest reproducibility PET study indicates that [¹¹C]DASB can be used to measure the serotonin transporter parameters with high reliability in receptor-rich brain regions.[4]

When the DASB neuroimages are analyzed the kinetic models suggested by Ichise and coworkers[12] can be employed to estimate the binding potential. A test-retest reproducibility experiment has been performed to evaluate this approach.[13]

Studies

Besides the studies listed below a few occupancy studies have been reported.[5]

DASB binding neuroimaging studies (patients compared to healthy control subjects).

What	Result	Subjects	Ref.
5-HTTLPR LALA serotonin transporter genotype	Increase in putamen	43/30	[14]
5-HTTLPR LALA serotonin transporter genotype	Increase in midbrain	19	[15]
5-HTTLPR LALA serotonin transporter genotype	No difference	63	[16]
Age	No effect found		[17] ([2])
Body mass index	Inverse correlation (?)	?	[18]
Seasonality	Higher in winter in putamen and caudate	54	[19]
Seasonality	Higher in fall and winter	88	[20]
NEO PI-R Neuroticism	Positive correlation in thalamus	31 males	[21]
Disease
Depressed during major depressive episodes	No difference found	20+20	[17]
Depressed with highly negativistic "dysfunctional attitudes" during major depressive episodes	Increase in prefrontal cortex, anterior cingulate, thalamus, bilateral caudate, and bilateral putamen	20(?)+20	[17]
Recovered depressed patients	No difference found	24+20 males	[22]
Unipolar depression	Increase in thalamus, insula and striatum	18+34	[23]
Unmedicated unipolar major depression	Reduced 5-HTT availability in the thalamus		[24]
TCI anxiety in unmedicated unipolar major depression	Reduced 5-HTT availability in the thalamus, midbrain and amygdala		[24]
Bipolar depression	Increase in thalamus, insula and striatum	18+34	[23]
Bipolar depression	Decrease in midbrain, amygdala, hippocampus, thalamus, putamen, and anterior cingulate cortex	18+41	[25]
Obsessive compulsive disorder	Reduction and correlation with severity in thalamus and midbrain	9+19	[26]
Alcoholism	No significant alteration	30 + 18	[27]
Parkinson's disease	Reduction in forebrain	5+8	[28]
Non-depressed Parkinson's disease	Decreased binding in caudate, midbrain, putamen, orbitofrontal cortex and (non-significantly) dorsolateral prefrontal cortex		[29]
Depressed Parkinson's disease patients	Increase in prefrontal and dorsolateral cortices	7+7	[30]
Drug/intervention
Abstinent MDMA ('Ecstasy') users	Global reduction	23+19	[31]
Former MDMA users and polydrug users	No significant difference in brain regions examined	12+9+19	[32]
Reduced synaptic serotonin (by rapid tryptophan depletion)	(small reduction in binding potential)	8	[33]
Lowering of brain serotonin (by acute tryptophan depletion)	No change observed	25 (14)	[34]

References

1. S. Houle; N. Ginovart; D. Hussey; J.H. Meyer; A.A. Wilson (October 2000). "Imaging the serotonin transporter with positron emission tomography: initial human studies with [¹¹C]DAPP and [¹¹C]DASB". European Journal of Nuclear Medicine and Molecular Imaging. 27 (11): 1719–22. doi:10.1007/s002590000365. PMID 11105830. S2CID 18932686.
2. Peter Brust; Swen Hess; Ulrich Müller; Zsolt Szabo (February 2006). "Neuroimaging of the Serotonin Transporter — Possibilities and Pitfalls" (PDF). Current Psychiatry Reviews. 2 (1): 111–149. doi:10.2174/157340006775101508. Archived from the original (PDF) on 2011-07-23. Retrieved 2008-01-23.
3. Alan A. Wilson; Nathalie Ginovart; Doug Hussey; Jeff Meyer; Sylvain Houle (July 2002). "In vitro and in vivo characterisation of [¹¹C]-DASB: a probe for in vivo measurements of the serotonin transporter by positron emission tomography". Nuclear Medicine and Biology. 29 (5): 509–515. doi:10.1016/S0969-8051(02)00316-5. PMID 12088720.
4. W. Gordon Frankle; Mark Slifstein; Roger N. Gunn; Yiyun Huang; Dah-Ren Hwang; E. Ashlie Darr; Rajesh Narendran; Marc Laruelle (May 1, 2006). "Estimation of Serotonin Transporter Parameters with ¹¹C-DASB in Healthy Humans: Reproducibility and Comparison of Methods". Journal of Nuclear Medicine. 47 (5): 815–826. PMID 16644752.
5. Jeffrey H. Meyer (March 2007). "Imaging the serotonin transporter during major depressive disorder and antidepressant treatment". Journal of Psychiatry & Neuroscience. 32 (2): 86–102. PMC 1810585. PMID 17353938.
6. Sudha Garg; Shankar R. Thopate; Richard C. Minton; Kimberly W. Black; Andrew J. H. Lynch; Pradeep K. Garg (September–October 2007). "3-Amino-4-(2-((4-[18F]fluorobenzyl)methylamino)methylphenylsulfanyl)benzonitrile, an F-18 fluorobenzyl analogue of DASB: synthesis, in vitro binding, and in vivo biodistribution studies". Bioconjug. Chem. 18 (5): 1612–1618. doi:10.1021/bc070112g. PMID 17705553.
7. Oya S, Choi SR, Hou C, et al. (April 2000). "2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine (ADAM): an improved serotonin transporter ligand". Nucl. Med. Biol. 27 (3): 249–54. doi:10.1016/s0969-8051(00)00084-6. PMID 10832081.
8. Zsolt Szabo; Una D. McCann; Alan A. Wilson; Ursula Scheffel; Taofeek Owonikoko; William B. Mathews; Hayden T. Ravert; John Hilton; Robert F. Dannals; George A. Ricaurte (May 1, 2002). "Comparison of (+)-¹¹C-McN5652 and ¹¹C-DASB as Serotonin Transporter Radioligands Under Various Experimental Conditions". Journal of Nuclear Medicine. 43 (5): 678–692. PMC 2078607. PMID 11994534.
9. Yiyun Huang, Dah-Ren Hwang, Raj Narendran, Yasuhiko Sudo, Rano Chatterjee, Sung-A Bae, Osama Mawlawi, Lawrence S. Kegeles, Alan A. Wilson, Hank F. Kung and Marc Laruelle (2002). "Comparative Evaluation in Nonhuman Primates of Five PET Radiotracers for Imaging the Serotonin Transporters: [¹¹C]McN 5652, [¹¹C]ADAM, [¹¹C]DASB, [¹¹C]DAPA, and [¹¹C]AFM". Journal of Cerebral Blood Flow & Metabolism. 22 (11): 1377–1398. doi:10.1097/00004647-200211000-00011. PMID 12439295.CS1 maint: multiple names: authors list (link)
10. Svend B. Jensen; Donald F. Smith; Dirk Bender; Steen Jakobsen; Dan Peters; Elsebet Ø. Nielsen; Gunnar M. Olsen; Jørgen Scheel-Krüger; Alan Wilson; Paul Cumming (May 2003). "[¹¹C]-NS 4194 versus [¹¹C]-DASB for PET imaging of serotonin transporters in living porcine brain". Synapse. 49 (3): 170–177. doi:10.1002/syn.10222. PMID 12774301. S2CID 35777731.
11. Nathalie Ginovart, Alan A. Wilson, Jeffrey H. Meyer, Doug Hussey and Sylvain Houle (2001). "Positron Emission Tomography Quantification of [¹¹C]-DASB Binding to the Human Serotonin Transporter: Modeling Strategies". Journal of Cerebral Blood Flow & Metabolism. 21 (11): 1342–1353. doi:10.1097/00004647-200111000-00010. PMID 11702049.CS1 maint: multiple names: authors list (link)
12. Masanori Ichise; Jeih-San Liow; Jian-Qiang Lu; Akihiro Takano; Kendra Model; Hiroshi Toyama; Tetsuya Suhara; Kazutoshi Suzuki; Robert B Innis; Richard E Carson (2003). "Linearized Reference Tissue Parametric Imaging Methods: Application to [¹¹C]DASB Positron Emission Tomography Studies of the Serotonin Transporter in Human Brain". Journal of Cerebral Blood Flow & Metabolism. 23 (9): 1096–1112. doi:10.1097/01.WCB.0000085441.37552.CA. PMID 12973026.
13. Jae Seung Kim; Masanori Ichise; Janet Sangare; Robert B. Innis (2006 China). "PET Imaging of Serotonin Transporters with [¹¹C]DASB: Test–Retest Reproducibility Using a Multilinear Reference Tissue Parametric Imaging Method". Journal of Nuclear Medicine. 47 (2): 208–214. PMID 16455625. Check date values in: |date= (help)
14. Nicole Praschak-Rieder; J. Kennedy; A. Wilson; D. Hussey; A. Boovariwala; M. Willeit; N. Ginovart; S. Tharmalingam; M. Masellis; S. Houle; Jeffrey H. Meyer (August 2007). "Novel 5-HTTLPR allele associates with higher serotonin transporter binding in putamen: a [¹¹C] DASB positron emission tomography study". Biological Psychiatry. 62 (4): 327–331. doi:10.1016/j.biopsych.2006.09.022. PMID 17210141. S2CID 46096787.
15. M. Reimold, M. N. Smolka, G. Schumann, A. Zimmer, J. Wrase, K. Mann, X.-Z. Hu, D. Goldman, G. Reischl, C. Solbach, H.-J. Machulla, R. Bares1 and A. Heinz (May 2007). "Midbrain serotonin transporter binding potential measured with [¹¹C]DASB is affected by serotonin transporter genotype". Journal of Neural Transmission. 114 (5): 635–9. doi:10.1007/s00702-006-0609-0. PMID 17225932. S2CID 9369923.CS1 maint: multiple names: authors list (link)
16. Murthy, NV; Selvaraj, S; Cowen, PJ; Bhagwagar, Z; Riedel, WJ; Peers, P; Kennedy, JL; Sahakian, BJ; et al. (August 2010). "Serotonin transporter polymorphisms (SLC6A4 insertion/deletion and rs25531) do not affect the availability of 5-HTT to [11C] DASB binding in the living human brain". NeuroImage. 52 (1): 50–54. doi:10.1016/j.neuroimage.2010.04.032. PMID 20406689. S2CID 2690593.
17. Jeffrey H. Meyer; Sylvain Houle; Sandra Sagrati; Anna Carella; Doug F. Hussey; Nathalie Ginovart; Verdell Goulding; James Kennedy; Alan A. Wilson (December 2004). "Brain Serotonin Transporter Binding Potential Measured With Carbon 11–Labeled DASB Positron Emission Tomography. Effects of Major Depressive Episodes and Severity of Dysfunctional Attitudes". Archives of General Psychiatry. 61 (12): 1271–9. doi:10.1001/archpsyc.61.12.1271. PMID 15583118.
18. Ryohei Matsumoto; H. Ito; H. Takahashi; H. Takano; T. Suhara (2008). "Inverse correlation between body mass index and serotonin transporter binding in human brain: A [¹¹C]DASB PET study". NeuroImage. 2, supplement 2: T161. doi:10.1016/j.neuroimage.2008.04.128. S2CID 53257175. Neuroreceptor Mapping 2008, The Seventh International Symposium on Functional Neuroreceptor Mapping of Living Brain
19. Jan Kalbitzer; David Erritzoe; Klaus K. Holst; Finn Å. Nielsen; Lisbeth Marner; Szabolcs Lehel; Tine Arentzen; Terry L. Jernigan; & Gitte M. Knudsen (28 January 2010). "Seasonal changes in brain serotonin transporter binding in short 5-HTTLPR-allele carriers but not in long-allele homozygotes". Biological Psychiatry. 67 (11): 1033–1039. doi:10.1016/j.biopsych.2009.11.027. PMID 20110086. S2CID 22393782.
20. Nicole Praschak-Rieder; Matthaeus Willeit; Alan A. Wilson; Sylvain Houle (September 2008). "Seasonal variation in human brain serotonin transporter binding". Archives of General Psychiatry. 65 (9): 1072–1078. doi:10.1001/archpsyc.65.9.1072. PMID 18762593.
21. Akihiro Takano; Ryosuke Arakawaa; Mika Hayashia; Hidehiko Takahashia; Tetsuya Suhara (September 2007). "Relationship between neuroticism personality trait and serotonin transporter binding". Biological Psychiatry. 62 (6): 588–592. doi:10.1016/j.biopsych.2006.11.007. PMID 17336939. S2CID 41664835.
22. Zubin Bhagwagar; Naga Murthy; Sudhakar Selvaraj; Rainer Hinz; Matthew Taylor; Sabrina Fancy; Paul Grasby; Philip Cowen (December 2007). "5-HTT Binding in Recovered Depressed Patients and Healthy Volunteers: A Positron Emission Tomography Study With [11C]DASB". The American Journal of Psychiatry. 164 (12): 1858–1865. doi:10.1176/appi.ajp.2007.06111933. PMID 18056241.
23. Dara M. Cannon, Masanori Ichise, Denise Rollis, Jacqueline M. Klaver, Shilpa K. Gandhi, Dennis S. Charney, Husseini K. Manji and Wayne C. Drevets (October 2007). "Elevated serotonin transporter binding in major depressive disorder assessed using positron emission tomography and [¹¹C]DASB; comparison with bipolar disorder". Biological Psychiatry. 62 (8): 870–877. doi:10.1016/j.biopsych.2007.03.016. PMID 17678634. S2CID 19689483.CS1 maint: multiple names: authors list (link)
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25. Maria A. Oquendo; Ramin S. Hastings; Yung-yu Huang; Norman Simpson; R. Todd Ogden; Xian-zhang Hu; David Goldman; Victoria Arango; Ronald L. Van Heertum; J. John Mann; Ramin V. Parsey (February 2007). "Brain Serotonin Transporter Binding in Depressed Patients With Bipolar Disorder Using Positron Emission Tomography". Archives of General Psychiatry. 64 (2): 201–208. doi:10.1001/archpsyc.64.2.201. PMC 3767993. PMID 17283287.
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27. Amira K. Brown; David T. George; Masahiro Fujita; Jeih-San Liow; Masanori Ichise; Joseph Hibbeln; Subroto Ghose; Janet Sangare; Daniel Hommer; Robert B. Innis (January 2007). "PET [¹¹C]DASB imaging of serotonin transporters in patients with alcoholism". Alcohol Clin Exp Res. 31 (1): 28–32. doi:10.1111/j.1530-0277.2006.00261.x. PMID 17207098.
28. Roger L Albin; Robert A. Koeppe; Nicolaas I. Bohnen; Kristine Wernette; Michael A. Kilbourn; Kirk A. Frey (2008). "Spared caudal brainstem SERT binding in early Parkinson's disease". Journal of Cerebral Blood Flow & Metabolism. 28 (3): 441–444. doi:10.1038/sj.jcbfm.9600599. PMID 18073772.
29. M. Guttman; I. Boileau; J. Warsh; J. A. Saint-Cyr; N. Ginovart; T. McCluskey; S. Houle; A. Wilson; E. Mundo; P. Rusjan; J. Meyer (May 2007). "Brain serotonin transporter binding in non-depressed patients with Parkinson's disease". European Journal of Neurology. 14 (5): 523–528. doi:10.1111/j.1468-1331.2007.01727.x. PMID 17437611. S2CID 30077418.
30. Isabelle Boileau; Jerry J. Warsh; Mark Guttman; Jean A. Saint-Cyr; Tina McCluskey; Pablo Rusjan; Sylvain Houle; Alan A. Wilson; Jeffrey H. Meyer; Stephen J. Kish (July 2008). "Elevated serotonin transporter binding in depressed patients with Parkinson's disease: A preliminary PET study with [(11)C]DASB". Movement Disorders. 23 (12): 1776–80. doi:10.1002/mds.22212. PMID 18661545. S2CID 33907854.
31. Una D McCann; Zsolt Szabo; Esen Seckin; Peter Rosenblatt; William B Mathews; Hayden T Ravert; Robert F Dannals; George A Ricaurte (2005). "Quantitative PET Studies of the Serotonin Transporter in MDMA Users and Controls Using [¹¹C]McN5652 and [¹¹C]DASB". Neuropsychopharmacology. 30 (9): 1741–1750. doi:10.1038/sj.npp.1300736. PMC 2034411. PMID 15841106.
32. Sudhakar Selvaraj; Rosa Hoshi; Zubin Bhagwagar; Naga Venkatesha Murthy; Rainer Hinz; Philip Cowen; H. Valerie Curran; Paul Grasby (2009). "Brain serotonin transporter binding in former users of MDMA ('ecstasy')". The British Journal of Psychiatry. 194 (4): 355–359. doi:10.1192/bjp.bp.108.050344. PMID 19336788.
33. Peter S. Talbot, W. Gordon Frankle, Dah-Ren Hwang, Yiyun Huang, Raymond F. Suckow, Mark Slifstein, Anissa Abi-Dargham & Marc Laruelle (2004). "Effects of reduced endogenous 5-HT on the in vivo binding of the serotonin transporter radioligand ¹¹C-DASB in healthy humans". Synapse. 55 (3): 164–175. doi:10.1002/syn.20105. PMID 15605360. S2CID 16602728.CS1 maint: multiple names: authors list (link)
34. Nicole Praschak-Riedera; Alan A. Wilson; Douglas Hussey; Anna Carella; Corie Wei; Nathalie Ginovart; Markus J. Schwarz; Johanna Zach; et al. (November 2005). "Effects of Tryptophan Depletion on the Serotonin Transporter in Healthy Humans". Biological Psychiatry. 58 (10): 825–830. doi:10.1016/j.biopsych.2005.04.038. PMID 16026765. S2CID 19327582.