Moderate chemical modifications of WAY-100635 improve the selectivity for 5-HT1A versus D4 receptors

Article abstract of DOI:10.1016/j.bmcl.2012.05.119

The selectivity for 5-HT_1A versus D₄ receptors is significantly increased when the basic side chain of WAY-100635 is replaced by a 4-phenylpiperazine (3e) or a 4-phenyl-1,2,3,6-tetrahydropyridine moiety (3i). The 4-phenyl-1,2,3,6-tet

Full text of DOI:10.1016/j.bmcl.2012.05.119

Bioorganic & Medicinal Chemistry Letters 22 (2012) 4550–4554
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Moderate chemical modifications of WAY-100635 improve the selectivity
for 5-HT1A versus D4 receptors
Floriane Mangin a, Sébastien Dilly a, Benoît Joly a, Jacqueline Scuvée-Moreau b, Jon Evans c,d
,
Vincent Setola c,d, Bryan L. Roth c,d, Jean-François Liégeois a,
⇑
a Laboratory of Medicinal Chemistry and Drug Research Center, University of Liège, Avenue de l’Hôpital, 1 (B36), B-4000 Liège 1, Belgium
b Laboratory of Pharmacology and GIGA-Neuroscience, University of Liège, Avenue de l’Hôpital, 1 (B36), B-4000 Liège 1, Belgium
c Department of Pharmacology School of Medicine and Division of Chemical Biology and Medicinal Chemistry, University of North Carolina Chapel Hill Medical School,
4072 Genetic Medicine Building, CB# 7365, Chapel Hill, NC 27599, USA
d National Institute of Mental Health Psychoactive Drug Screening Program, Department of Pharmacology, University of North Carolina Chapel Hill Medical School,
Chapel Hill, NC 27599, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The selectivity for 5-HT1A versus D4 receptors is significantly increased when the basic side chain of WAY-
100635 is replaced by a 4-phenylpiperazine (3e) or a 4-phenyl-1,2,3,6-tetrahydropyridine moiety (3i).
The 4-phenyl-1,2,3,6-tetrahydropyridine compounds (3i–l) have a higher affinity for 5-HT1A receptors
than do the corresponding unsubstituted phenylpiperazine analogues (3e–h). Compounds 3e and 3i
appear to be selective for 5-HT1A receptors over other relevant receptors and still behave as neutral
antagonists.
Received 19 April 2012
Revised 30 May 2012
Accepted 30 May 2012
Available online 7 June 2012
Keywords:
Amide
Ó 2012 Elsevier Ltd. All rights reserved.
Antagonist
Dopamine
Receptor
Serotonin
WAY-100635, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl]-
N-(2-pyridinyl)-cyclohexane carboxamide (3a) (Fig. 1), is widely
used in vitro and in vivo as an antagonist of 5-HT1A receptors.1 In
terms of pharmacological tools and pharmacological investiga-
tions, the ideal reference molecule would be highly selective for
its target over other related and non-related targets. However
WAY-100635 displays affinity for and activity at D4 dopamine
receptors, and that ‘off-target’ activity confounds its use in phar-
macological studies, particularly when both receptors are present.2
In a rat behavioural model, WAY-100635 produces discriminative
stimulus effects via D4 receptor activation.3 Nevertheless, WAY-
100635 exhibits selectivity for 5-HT1A receptors versus D4 recep-
tors in in vitro activity models.4 In addition to our study, others
have made5–7 or are attempting to synthesize8,9 more selective
5-HT1A receptor ligands for such applications as brain imaging
and animal studies.
limited chemical modifications of this compound were intended
by introducing fragments that we found more favourable for inter-
action with 5-HT1A sites than for D4 receptors. The resulting com-
pounds were tested in radioligand competition binding assays to
determine their affinity for both receptors. Functional assays were
also performed to assess ligand efficacy at both receptors using
in vitro procedures. Following this biological evaluation, two com-
pounds, 3e and 3i, each displaying improved selectivity for 5-HT1A
versus D4 receptors, were selected for further biological evaluation.
N
OMe
N
In the present work, we attempted various chemical modifica-
tions of the WAY-100635 structure in order to improve its 5-HT1A
versus D4 selectivity. In a previous series of 4-arylpiperazine-
ethyl-carboxamide derivatives, we reported that some chemical
modifications affected 5-HT1A and/or D4 affinity.10 Therefore,
N
N
O
⇑
Corresponding author. Tel.: +32 43 66 43 77; fax: +32 43 66 43 62.
E-mail address: JF.Liegeois@ulg.ac.be (J.-F. Liégeois).
Figure 1. Chemical structure of WAY-100635 (3a).
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.05.119

F. Mangin et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4550–4554
4551
O
O
a
Cl
+
Cl
N
H
N
H2N
N
Cl
b
R1
R1
Y
Y
X
O
X
c
N
N
N
H
N
N
H
N
2a-c
1a-c
d
R1
Y
X
N
N
N
3a-l
O
R2
Scheme 1. Reagents and conditions: (a) Et3N, dioxane, 2–3 h, rt, (b) 4-arylpiperazine or 4-phenyl-1,2,3,6-tetrahydropyridine, Et3N, dioxane, 1–2 h, reflux, (c) LiAlH4, Et2O,
5 min at 0 °C and 1 h at reflux, (d) R2-COCl, Et3N, EtOAc, 2 h, rt, R1 = H, 2-OMe; R2 = –C6H11, –2-C10H7, –1-C10H7, –2-C8H5N2; X–Y: C@CH or N–CH2.
Towards that end, an extended binding profile and electrophysio-
logical measurements on rat brain slices were performed.
The synthetic pathway is illustrated in Scheme 1. The appropri-
ate 4-arylpiperazine or 4-phenyl-1,2,3,6-tetrahydropyridine (THP)
moiety reacts with the key intermediate N-(2-pyridyl)-2-chloro-
acetamide to give the amide analogues (1a–c) in a one pot synthe-
sis. The corresponding substituted acetamide derivative after
purification is treated with LiAlH4 to give the corresponding
amines (2a–c). After isolation, the crude amines are treated with
the appropriate acid chloride in the presence of an excess of trieth-
ylamine to give the target compounds (3a–l). In some cases, the
compound is isolated as a salt. All synthesized compounds (3a–l)
were subjected to 1H and 13C NMR, IR and elemental analysis be-
fore biological testing to confirm their chemical structure and/or
purity.
In vitro binding experiments were conducted on human cloned
receptors expressed in CHO and Sf9 cells and isolated as membrane
preparations for 5-HT1A and D4 receptors, respectively. The radioli-
gands used were [3H]-8-OH-DPAT (ꢀ0.25 nM) and [3H]-YM-
09151-2 (ꢀ0.2 nM) for 5-HT1A and D4 receptors, respectively.
Experimental procedures for membrane filtration and radioactivity
counting were performed using a described methodology.11 The
results are reported in Table 1.
WAY-100635 (3a) exhibited a high affinity for 5-HT1A receptors
(Table 1). In this series, the replacement of the cyclohexyl moiety
by a 2-naphthyl (3b), a 1-naphthyl (3c) and a quinoxaline (3d) re-
duced the affinity by approximately 6-, 7- and 10-fold, respec-
tively. The presence of an unsubstituted phenylpiperazine (3e–h)
instead of the 4-(2-methoxyphenyl)piperazine tended to reduce
the affinity up to 30-fold except when the acyl group was a cyclo-
hexyl (3e). When the 4-phenylpiperazine was replaced by a 4-phe-
nyl-1,2,3,6-THP (3i–l), the affinity of the cyclohexyl analogue (3i)
was also only 2-fold lower than that of WAY-100635 (3a), while
the 2-naphthyl (3j), the 1-naphthyl (3k) and the quinoxaline (3l)
derivatives exhibited a higher affinity than did the corresponding
4-phenylpiperazine analogues (3f–h).
WAY-100635 (3a) displayed a significant affinity for D4 receptor
sites (Table 1). In the 2-methoxy series, the presence of a 2-naph-
thyl (3b) reduced the affinity, while the 1-naphthyl led to an ana-
logue (3c) with similar affinity than WAY-100635, and the
quinoxaline (3d) appeared even more favourable in terms of inter-
action with D4 receptors. Except for the quinoxaline analogue (3h),
the replacement of the 2-methoxyphenylpiperazine by an unsub-
stituted phenylpiperazine (3e–h) led to a reduction of the affinity
for D4 receptors by 4- to 18-fold. Compounds with a 4-phenyl-
1,2,3,6-THP moiety (3i–l) also exhibited lower affinity for D4 recep-
tors, with the quinoxaline analogue (3l) being an exception in that
it showed higher affinity for D4 sites.
In our experiments, WAY-100635 (3a) showed approximately
200-fold selectivity for 5-HT1A receptors versus D4 receptors (Table
1). The chemical modifications of the acyl moiety were mostly
unfavourable, resulting in lower 5-HT1A/D4 selectivity ratios for
all compounds except for the 2-naphthyl analogue (3b). The quin-
oxaline moiety appeared less interesting in this series in terms of
selectivity because the corresponding analogues (3d, 3h, 3l) exhib-
ited increased D4 affinity. When the 2-methoxyphenylpiperazine
was replaced by a 4-phenylpiperazine, the cyclohexyl analogue
(3e) showed a 5-HT1A/D4 selectivity ratio of approximately 800,
while the other groups on the acyl moiety did not increase selectiv-
ity (Table 1). In the THP series (3i–l), the cyclohexyl analogue (3i)
also presented a higher selectivity (approximately 800-fold) com-
pared with the naphthyl and quinoxaline groups and, notably, with
WAY-100635 (3a). Thus, the selectivity ratio between 3e and 3i
and the parent compound was approximately equal to four.
To explain such modifications in terms of affinity, the pKa or
lipophilicity values were examined (Table 1). In the present series,
the evolution of the affinity for 5-HT1A receptors does not correlate
with the variations observed in pKa or lipophilicity. It is known that
the basicity of nitrogen in different molecules can be an important
element in terms of interaction with acidic residues in GPCR’s.12,13
The increased basicity observed with THP analogues (3i–l) does not
seem to be a favourable element, as the affinities are slightly

4552
F. Mangin et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4550–4554
Table 1
In vitro binding evaluation of WAY-100635 (3a) and analogues (3b–l) on cloned 5-HT1A and D4 receptors and physicochemical characteristics
R1
Y
X
N
N
N
O
R2
R1
R2
X–Y
5-HT1A
D4
Selectivityb
pKa
Logk’IAMd
a
a
c
Compd
3a
3b
3c
3d
3e
3f
3g
3h
3i
2-OMe
2-OMe
2-OMe
2-OMe
H
H
H
H
H
H
H
H
–C6H11
N–CH2
N–CH2
N–CH2
N–CH2
N–CH2
N–CH2
N–CH2
N–CH2
C@CH
C@CH
C@CH
C@CH
0.25 0.04
1.61 0.42
1.89 0.23
2.48 0.46
1.21 0.21
16.29 2.37
35.85 3.2
36.19 5.1
0.51 0.04
8.36 1.86
14.01 1.65
8.27 1.14
52 9.4
184 26
69 17
208
114
37
6
782
50
7.27
7.29
7.31
7.06
6.93
6.95
6.96
6.72
7.79
7.81
7.82
7.58
3.03
3.57
3.26
2.61
2.68
3.48
3.27
3.06
3.84
4.36
4.07
3.33
–2-C10H7
–1-C10H7
–C8H5N2
–C6H11
–2-C10H7
–1-C10H7
–C8H5N2
–C6H11
15 1.5
946 144
807 35
550 41
56.8 2.95
385 28
291 33
252 17
15
1.6
755
35
18
4
3j
3k
3l
–2-C10H7
–1-C10H7
–C8H5N2
35
7
a
b
c
Ki in nM; mean SEM, n P 3.
The 5-HT1A/D4 selectivity is obtained by dividing D4 affinity by 5-HT1A affinity.
pKa values predicted by the SPARC on-line calculator.18
d
For experimental details see Supplementary data.
reduced compared with WAY-100635 analogues (3a–d). On the
other hand, the lipophilicity of THP analogues (3i–l) is increased
and thus could compensate for the negative impact of the in-
creased basic character. Regarding the reduced affinity for D4
receptors, these parameters do not seem to be the only ones in-
volved. Other structural features should be responsible for these
variations of affinity for the examined receptors. Previously, the
THP fragment was reported to be interesting in another series,10
and an explanation was suggested involving a spatial orientation
Table 2
In vitro evaluation of 5-HT1A antagonist and D4 agonist activity by a screening at
10À6
M
R1
Y
X
N
favourable to a CH-p interaction with a phenyl residue of the
N
N
5-HT1A receptor sites.14 In the present work, the THP analogues
(3i–l) also exhibited increased interaction with 5-HT1A receptor
sites compared with the corresponding unsubstituted phenylpip-
erazine analogues (3e–h). Moreover, the lower affinity of the
unsubstituted phenylpiperazine and THP compounds for 5-HT1A
receptors could be explained by a possible hydrogen bond between
the methoxy group and residues of the binding sites such as a ser-
ine residue. The absence of the methoxy also significantly reduced
the affinity for D4 receptors, except when the acyl group contained
a nitrogen atom (R2 in Scheme 1), thus suggesting possible addi-
tional hydrogen bonds between the ligands and the D4 receptors.
Subsequently, we addressed whether the compounds retained
WAY-100635-like 5-HT1A antagonist efficacy. As reported in Table 2,
the intrinsic activity of these compounds on 5-HT1A receptors was
not affected. Moreover, positive efficacy at D4 receptors was detected
for WAY-100635 as well as for the newly synthesized analogues.
Following this preliminary evaluation, two compounds, 3e and
3i, showed a higher selectivity for 5-HT1A versus D4 receptors
and were selected for further biological evaluation. Both molecules
are not substituted on the distal phenyl ring and thus, this fact
could constitute an advantage in comparison with WAY-100635.
Indeed, WAY-100635 is known to be O-desmethylated and deacy-
lated.15,16 In this preliminary investigation, we did not explore this
aspect. Nevertheless, future developments should integrate the
pharmacokinetic and metabolic properties of newly designed or
synthesized compounds. Thus, the selectivity for 5-HT1A receptors
over a variety of other relevant receptors was determined. The
O
R2
a,b
c,d
Compd
R1
R2
–C6H11
–2-C10H7
–1-C10H7
–C8H5N2
–C6H11
–2-C10H7
–1-C10H7
–C8H5N2
–C6H11
–2-C10H7
–1-C10H7
–C8H5N2
X–Y
5-HT1A
D4
3a
3b
3c
3d
3e
3f
3g
3h
3i
2-OMe
2-OMe
2-OMe
2-OMe
H
H
H
H
H
H
H
H
N–CH2
N–CH2
N–CH2
N–CH2
N–CH2
N–CH2
N–CH2
N–CH2
C@CH
C@CH
C@CH
C@CH
101 (À6)
101 (À4)
104 (À7)
96 (À5)
104 (À4)
74 (À2)
64 (À4)
61 (2)
101 (3)
71 (À5)
83 (À4)
61 (7)
90 (À8)
60 (10)
97 (À14)
83 (1)
65 (À4)
18 (1)
53 (3)
64 (9)
76 (3)
15 (10)
75 (3)
3j
3k
3l
62 (19)
a
b
c
% inhibition of control agonist response.
In brackets, agonist effect expressed as % of control agonist response.
% of control agonist response.
d
In brackets, antagonist effect expressed as
response.
% inhibition of control agonist
binding profile is reported in Table 3. Other experimental condi-
tions for 5-HT1A and D4 determinations particularly cell types used
might explain the difference in Ki values between Table 1 and
Table 3. In comparison with the data presented in Table 1, the
selectivity for 5-HT1A versus D4 receptors appeared inferior with

F. Mangin et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4550–4554
4553
Table 3
In vitro binding profile of target compounds, 3e and 3i, in comparison with WAY-100635a,b,c
Compd
5-HT1A
5-HT2A
5-HT2B
5-HT7
a1A
a1B
D4
WAY-100635(3a)
3e
3i
0.6 (2.2)d
1.85
0.69
6260d
180
54
24d
327
105
>10,000d
198
60
20d
584
39
322d
1051
296
16d
246
55
a
For assay conditions and assay protocols see http://pdsp.med.unc.edu/pdspw/binding.php.
b
The primary testing of the compounds on a number of receptors (serotonin receptor subtypes: 5-HT1B, 5-HT1D, 5ht1e, 5-HT2C, 5-HT3, 5-ht5a, 5-HT6; adrenoceptor subtypes:
2B, b1, b2, b3; benzodiazepine rat brain site; dopamine receptor subtype D1, D5; dopamine transporter (DAT); GABAA; H3; muscarinic receptor subtypes M1–5) showed
M). On other receptors (dopamine receptor subtypes D2 and D3; sigma receptor subtypes 1 and 2) where the compounds showed >50% inhibition at
M the Ki values were at least a factor of 100 greater than those for the 5-HT1A receptor.
a2A, a
<50% inhibition at 10
l
r
r
10
l
c
Results are presented as apparent equilibrium constant (Ki) in nM and are the mean of two experiments.
Data taken from NIMH-PDSP Ki database (http://pdsp.med.unc.edu/pdsp.php) or previously reported.8,9
d
shown). Similarly to WAY-100635, both compounds behave as
neutral antagonists in this pharmacological procedure.
In conclusion, with these chemical modifications, we have iden-
tified substitutions that increase selectivity for 5-HT1A versus D4
receptors and also versus other receptors, such as the adrenoceptor
subtypes. In addition, the analogues retain WAY-100635-like
5-HT1A receptor antagonist activity. Based on the present and
previously reported results, future investigations, including in sil-
ico approaches, should illuminate new chemical modifications for
developing improved pharmacological tools.
Acknowledgments
The technical assistance of S. Counerotte, J. Ghiotto, L. Massotte
and J. Widart for elemental analyses, NMR spectra, electrophysio-
logical recordings and mass spectra, respectively, is gratefully
acknowledged. This study is supported in part by grants of the
Fonds de la Recherche Scientifique-FNRS (F.R.S.-FNRS) and the
Fonds Spéciaux pour la Recherche of the University of Liège
(Belgium). J.-F.L. is Research Director of the F.R.S.-FNRS. B.J. was
supported by a Research Student fellowship from the Faculty of
Medicine of the University of Liège. Extended radioligand binding
assays on 3e and 3i were performed by the NIMH Psychoactive
Drug Screening Program Contract to BLR.
Figure 2. In vitro extracellular recording of a dorsal raphe serotonergic neuron. The
inhibitory effect of 8-OH-DPAT is reversed by the simultaneous application of 3i.
values equal approximately to 11, 132 and 80 for WAY-100635, 3e
and 3i, respectively. Nevertheless, in terms of selectivity for 5-HT1A
versus D4 receptors, 3e and 3i appeared more discriminating than
did WAY-100635, with a selectivity ratio increasing from 4 to 11
and from 4 to 4.5, respectively. Otherwise, compound 3e has lower
Supplementary data
affinity for several receptors (a1A, a1D, 5-HT2B) than does WAY-
100635. However, an increase in 5-HT7 receptor affinity is ob-
served for both compounds (3e, 3i), but it remains approximately
60–120 times lower than the affinity for the 5-HT1A receptor. Inter-
estingly, it appears that the THP analogue 3i possesses a higher
affinity for all receptors than does 3e. An increase in affinity for
5-HT1A receptors was previously observed10 and discussed14 in an-
other series.
Furthermore, the two most selective compounds (3e, 3i) were
evaluated in an electrophysiological procedure to confirm their
5-HT1A receptor antagonism. It is well known that the firing rate
of dorsal raphe serotonergic neurons is inhibited by 5-HT1A ago-
nists such as 8-OH-DPAT,17 and that this effect is blocked or
reversed by 5-HT1A antagonists such as WAY-100635.1 In this
work, dorsal raphe serotonergic neurons were recorded in rat brain
slices, and the ability of the two compounds to reverse the effect of
8-OH-DPAT was evaluated. Superfusion of 8-OH-DPAT (20 nM) in-
duced a progressive decrease of the firing rate of dorsal raphe sero-
tonergic neurons. A complete inhibition of firing was observed
after 5–10 min. Compounds (3e) and (3i) both reversed the inhib-
itory effect of 8-OH-DPAT when superfused at a concentration of
100 nM. At this concentration, reversal ranged from 44% to 73%
for compound (3e) (n = 3) and from 44% to 99% for compound
(3i) (n = 3) (Fig. 2). Furthermore, when superfused alone at concen-
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2012.05.
119.
References and notes
1. Forster, E. A.; Cliffe, I. A.; Bill, D. J.; Dover, G. M.; Jones, D.; Reilly, Y.; Fletcher, A.
Eur. J. Pharmacol. 1995, 281, 81.
2. Chemel, B. R.; Roth, B. L.; Armbruster, B.; Watts, V. J.; Nichols, D. E.
Psychopharmacology 2006, 188, 244.
3. Marona-Lewicka, D.; Nichols, D. E. Behav. Pharmacol. 2009, 20, 114.
4. Martel, J. C.; Leduc, N.; Ormiere, A. M.; Faucillon, V.; Danty, N.; Culie, C.; Cussac,
D.; Newman-Tancredi, A. Eur. J. Pharmacol. 2007, 574, 15.
5. Marchais-Oberwinkler, S.; Nowicki, B.; Pike, V. W.; Halldin, C.; Sandell, J.; Chou,
Y. H.; Gulyas, B.; Brennum, L. T.; Farde, L.; Wikström, H. V. Bioorg. Med. Chem.
2005, 13, 883.
6. Childers, W. E., Jr.; Havran, L. M.; Asselin, M.; Bicksler, J. J.; Chong, D. C.; Grosu,
G. T.; Shen, Z.; Abou-Gharbia, M. A.; Bach, A. C., 3rd; Harrison, B. L.; Kagan, N.;
Kleintop, T.; Magolda, R.; Marathias, V.; Robichaud, A. J.; Sabb, A. L.; Zhang, M.
Y.; Andree, T. H.; Aschmies, S. H.; Beyer, C.; Comery, T. A.; Day, M.; Grauer, S.
M.; Hughes, Z. A.; Rosenzweig-Lipson, S.; Platt, B.; Pulicicchio, C.; Smith, D. E.;
Sukoff-Rizzo, S. J.; Sullivan, K. M.; Adedoyin, A.; Huselton, C.; Hirst, W. D. J. Med.
Chem. 2010, 53, 4066.
7. Khatri, M.; Rai, S. K.; Alam, S.; Vij, A.; Tiwari, M. Bioorg. Med. Chem. 2009, 17, 1890.
8. Al Hussainy, R.; Verbeek, J.; van der Born, D.; Booij, J.; Herscheid, J. K. Eur. J. Med.
Chem. 2011, 46, 5728.
9. Al Hussainy, R.; Verbeek, J.; van der Born, D.; Braker, A. H.; Leysen, J. E.; Knol, R.
J.; Booij, J.; Herscheid, J. K. J. Med. Chem. 2011, 54, 3480.
10. Graulich, A.; Léonard, M.; Résimont, M.; Huang, X. P.; Roth, B. L.; Liégeois, J.-F.
Aust. J. Chem. 2010, 63, 56.
trations ranging from 1 nM to 1
lM, neither compound induced an
inhibition of firing, confirming a lack of agonist activity (data not

4554
F. Mangin et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4550–4554
11. Liégeois, J.-F.; Eyrolles, L.; Ellenbroek, B. A.; Lejeune, C.; Carato, P.; Bruhwyler,
J.; Géczy, J.; Damas, J.; Delarge, J. J. Med. Chem. 2002, 45, 5136.
12. Hibert, M. F.; Trumpp-Kallmeyer, S.; Bruinvels, A.; Hoflack, J. Mol. Pharmacol.
1991, 40, 8.
13. Trumpp-Kallmeyer, S.; Hoflack, J.; Bruinvels, A.; Hibert, M. J. Med. Chem. 1992,
35, 3448.
16. Pike, V. W.; Halldin, C.; Wikstrom, H.; Marchais, S.; McCarron, J. A.; Sandell, J.;
Nowicki, B.; Swahn, C. G.; Osman, S.; Hume, S. P.; Constantinou, M.; Andree, B.;
Farde, L. Nucl. Med. Biol. 2000, 27, 449.
17. Aghajanian, G. K.; Sprouse, J. S.; Sheldon, P.; Rasmussen, K. Ann. N.Y. Acad. Sci.
1990, 600, 93.
18. Hilal, S. H.; El-Shabrawy, Y.; Carreira, L. A.; Karickhoff, S. W.; Toubar, S. S.; Rizk,
M. Talanta 1996, 43, 607.
14. Dilly, S.; Graulich, A.; Liégeois, J.-F. Bioorg. Med. Chem. Lett. 2010, 20, 1118.
15. Cliffe, I. A. Nucl. Med. Biol. 2000, 27, 441.