Cyclopentadienyltricarbonylrheniumbenzazepines: Synthesis and binding affinity

Article abstract of DOI:10.1016/S0960-894X(00)00185-2

Analogues of the benzazepine dopamine D₁ receptor antagonist SCH-23390 incorporating the cyclo-pentadienyltricarbonyl-rhenium (CPTR) moiety were synthesized and evaluated pharmacologically. The CPTR derivatives retained affinity (0.3-2.9 nM) an

Full text of DOI:10.1016/S0960-894X(00)00185-2

Bioorganic & Medicinal Chemistry Letters 10 (2000) 1113±1115
Cyclopentadienyltricarbonylrheniumbenzazepines:
Synthesis and Binding Anityy
Gilles Tamagnan, a,* Ronald M. Baldwin, a Nora S. Kula, b Ross J. Baldessarini b
and Robert B. Innis a
aYale University, School of Medicine, VA Connecticut HCS, (116A2), 950 Campbell Avenue, West Haven, CT 06516, USA
bDepartment of Psychiatry & Neuroscience Program, Harvard Medical School, Mailman Research Center,
McLean Division of Massachusetts General Hospital, Belmont, MA 02478, USA
Received 22 February 2000; accepted 14 March 2000
AbstractÐAnalogues of the benzazepine dopamine D1 receptor antagonist SCH-23390 incorporating the cyclo-pentadienyl-
tricarbonyl-rhenium (CPTR) moiety were synthesized and evaluated pharmacologically. The CPTR derivatives retained anity
(0.3±2.9 nM) and D1 selectivity of the parent compound, supporting their use as neuropharmacological surrogates for 99mTc-
labeled SPECT radiopharmaceuticals. # 2000 Elsevier Science Ltd. All rights reserved.
Introduction
complexes traditionally used to bind 99mTc by chela-
tion.13 A problem for development of useful 99mTc-
labeled compounds as imaging agents is the lack of
compounds containing a comparable but stable isotope
to serve as surrogates for pharmacological assessment.
In general, the structural and biochemical properties of
technetium correlate well with those of rhenium,14,15 so
that this represent a fruitful avenue of research.16
Single photon emission computed tomography (SPECT)
is a cost-e€ective technique for functional imaging of the
central nervous system. SPECT has been used to study
interactions of speci®c radioligands and unlabeled drugs
with brain receptor and transporter sites for clinical
neuropharmacological studies.1 3 Radioligands for this
purpose are usually labeled with 99mTc or 123I. Two Tc-
labeled complexes, TRODAT-1 and technepine, have
been reported to retain selective binding to the dop-
amine transporter, but their in vivo labeling of cerebral
targets includes a high proportion of nonspeci®c label-
ing.4,5 Moreover, 99mTc-labeled SPECT ligands that are
highly selective for cerebral neurotransmitter receptor
sites are still uncommon.
The benzazepine (+)-N-methyl-1-phenyl-2,3,4,5-tetra-
(SCH-
hydro-[1H-3]-7-chloro-8-hydroxybenzazepine
23390) is a highly selective antagonist for D1-like (D1/5
)
dopamine receptors. In radiolabeled form, [3H]SCH-
23390 is a standard laboratory radioligand for D1 recep-
tor labeling, and it has been labeled with 11C for PET
imaging.17,18 TISCH, an iodinated analogue of SCH-
23390, also has been synthesized, characterized, labeled
with 123I, and evaluated in vivo as a D1-selective SPECT
radioligand in non human primate.19 We now report the
preparation of rhenium containing cyclopentadienyl-
tricarbonyl derivatives targeted to dopamine D1 and
assessments of their receptor binding properties.
Limitations to developing 99mTc-labeled receptor ligands
include the bulkiness or charge properties of relatively
large chelation moieties required to complex technetium.
In 1992, Wenzel and others reported treating a ligand to
be labeled with [99mTc]-TcO4 in the presence of a car-
bonyl donor to give the cyclopentadienyltricarbonyl-
technetium analogue.6 12 Such derivatives are likely to
be less sterically hindered and less polar than other
Synthesis of benzazepine derivatives for D1 receptor
A route to benzazepines of type 8a was described that
involved reacting the styrene oxide 3a with the primary
amine 2 to give 4a (Scheme 1).19 However, we found
that the major product of this reaction was the dialky-
lated tertiary amine 5a (60% yield), with a low yield
*Corresponding author. Tel.: +1-203-931-5711 ext. 3109; fax: +1-
203-937-3897; e-mail: gilles.tamagnan@yale.edu
ySome of this work was presented at the Fifth International Sympo-
sium on Technetium in Chemistry and Nuclear Medicine, Bressanone,
Italy, 6±9 September 1998.
0960-894X/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(00)00185-2

1114
G. Tamagnan et al. / Bioorg. Med. Chem. Lett. 10 (2000) 1113±1115
Scheme 1.
(35%) of the desired secondary amine 4a. Since this
route (Scheme 1) gave a low yield, we investigated a new
synthetic method to obtain 8a or 8b (Scheme 2).
Pharmacological Activities
The synthesized CPTR analogues of the D1-selective
compound SCH-23390 (10a and 10b) were evaluated for
anity (indicated by inhibitory potency, Ki) in compe-
titive radioreceptor binding assays with tissue homo-
geates prepared from rat forebrain. Preliminary
comparisons of SCH-23390 with its 20- and 30-Br deri-
vatives indicated substantial retention of D1 anity and
selectivity (Table 1). Moreover, the corresponding 20-
and 30-CPTR derivatives 10a and 10b retained a high
degree of selectivity (900- to 3,460-fold) for D1-like over
D2-like receptors in homogenates of rat corpus stria-
tum, with only moderate loss of D1 anity (Table 1).
For comparison, SCH-23390 itself showed >10,000-
fold D1-over-D2 selectivity (Table 1). Novel com-
pounds 10a and 10b showed even lower anity to
cerebral 5-HT2A and 5-HT2C receptors than the parent
compound SCH-23390.
A solution of the substituted benzyl chloride 1 in N,N-
dimethylformamide was treated with aq KCN to give an
intermediate phenylacetonitrile,20 which was reduced
directly to the corresponding phenethylamine 2 with
AlH3.21 The primary amine 2 was then N-mono-
methylated with methyl formate, followed by reduction
with borane/THF to give 6 in 95% yield. Condensation
of the 2- or 3-bromostyrene oxide 3a (2-) or 3b (3-) with
the amine 6 in re¯uxing xylene gave the tertiary amines
7a or 7b in 90% yield. Their cyclization with con-
centrated H2SO4 at 0 ꢀC and O-demethylation with
BBr3 gave 8a and 8b in 40% yield. Addition of n-BuLi
at 78 ꢀC, followed by addition of the acyl chloride 9
led to the ®nal desired CPTR-containing organometalic
benzazepine derivatives 10a and 10b.
Scheme 2.
Table 1. Potency (mean Ki Æ SE, nM) of SCH-23390 and its CPTR derivatives at dopamine and serotonin receptors in homogenates of caudate-
putamen tissue from rat brain
Test agent
D1-like
D2-like
5-HT2A
5-HT2C
(+)-SCH-23390
0.12 Æ 0.02
0.70 Æ 0.08
0.26 Æ 0.02
0.61 Æ 0.07
2.89 Æ 0.32
1210 Æ 100
583 Æ 55
1120 Æ 75
549 Æ 48
>10,000
10.8 Æ 1.6
22.1 Æ 3.0
8.50 Æ 0.95
17.3 Æ 1.2
227 Æ 17.7
12.5 Æ 0.63
11.8 Æ 0.8
2.08 Æ 0.30
28.5 Æ 5.5
106 Æ 17.5
( Æ )-20-Br-SCH-23390
( Æ )-30-Br-SCH-23390
( Æ )-20-CPTR-SCH-23390 (8a)
( Æ )-30-CPTR-SCH-23390 (8b)

G. Tamagnan et al. / Bioorg. Med. Chem. Lett. 10 (2000) 1113±1115
1115
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These results indicate that compounds containing the
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Acknowledgements
This work was supported in part by funds from the
department of Veterans A€airs (Schizophrenia
Research Center) and the US Public Health Service-NIH
(MH-30929, MH-34006, and MH-47370), the Bruce J.
Anderson Foundation, and the McLean Hospital Pri-
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