The preparation and characterization of functionalized carboranes and Re/Tc-metallocarboranes as platforms for developing molecular imaging probes: Structural and cage isomerism studies

Article abstract of DOI:10.1016/j.ica.2012.03.017

A study of the structure and reactivity of a series of carborane ligands [(RC₂B₉H₁₁)^-] towards Re(I) and ^99mTc(I) was undertaken in which the arising products [(M(CO) ₃RC₂B₉H₁₀)^-, M = Re, ^99mTc] can be used as platforms to develop organometallic molecular imaging agents. Synthetic methods are reported that produce good yields of the target ligands and metal complexes where the organometallic complexes were prepared in aqueous solvents at both the macroscopic scale and at the tracer level. NMR and X-ray crystallography studies confirmed the structures of the closo and nido-ligands and demonstrated that the rhenacarborane complexes exist as 3,1,2 and/or 2,1,8 isomers where the product distribution depends upon on the steric bulk and electronic influence of the substituent linked to the carbon atom of the carborane cage. Experiments at the tracer level with ^99mTc(I) demonstrated for one ligand a difference in the ratio of isomers produced and the reactivity of the ligands compared to that for Re(I). Data is also presented to show for the first time that a 3,1,2-technetium carborane forms initially during radiolabeling and then upon heating isomerizes to the more stable 2,1,8 isomer. The comparable process is not observed for rhenium. The log D values for the technetium complexes were also measured and are within the range needed to cross the blood-brain-barrier making the reported compounds viable candidates for imaging key targets in the central nervous system.

Full text of DOI:10.1016/j.ica.2012.03.017

Inorganica Chimica Acta 389 (2012) 159–167
Contents lists available at SciVerse ScienceDirect
Inorganica Chimica Acta
journal homepage: www.elsevier.com/locate/ica
The preparation and characterization of functionalized carboranes
and Re/Tc-metallocarboranes as platforms for developing molecular
imaging probes: Structural and cage isomerism studies
⇑
Anika S. Louie, Laura E. Harrington, John F. Valliant
Department of Chemistry and Chemical Biology, McMaster University, 1280 Main St. W. Hamilton, Ontario, Canada L8S 4M1
a r t i c l e i n f o
a b s t r a c t
A study of the structure and reactivity of a series of carborane ligands [(RC2B9H11)À] towards Re(I)
and 99mTc(I) was undertaken in which the arising products [(M(CO)3RC2B9H10)À, M = Re, 99mTc] can be
used as platforms to develop organometallic molecular imaging agents. Synthetic methods are reported
that produce good yields of the target ligands and metal complexes where the organometallic complexes
were prepared in aqueous solvents at both the macroscopic scale and at the tracer level. NMR and X-ray
crystallography studies confirmed the structures of the closo and nido-ligands and demonstrated that the
rhenacarborane complexes exist as 3,1,2 and/or 2,1,8 isomers where the product distribution depends
upon on the steric bulk and electronic influence of the substituent linked to the carbon atom of the car-
borane cage. Experiments at the tracer level with 99mTc(I) demonstrated for one ligand a difference in the
ratio of isomers produced and the reactivity of the ligands compared to that for Re(I). Data is also pre-
sented to show for the first time that a 3,1,2-technetium carborane forms initially during radiolabeling
and then upon heating isomerizes to the more stable 2,1,8 isomer. The comparable process is not
observed for rhenium. The logD values for the technetium complexes were also measured and are within
the range needed to cross the blood–brain-barrier making the reported compounds viable candidates for
imaging key targets in the central nervous system.
Article history:
Available online 10 March 2012
Dedicated to Prof. Jon Zubieta
Keywords:
Carboranes
Isomerization
Molecular imaging
Technetium-99m
Radiolabeling
Ó 2012 Elsevier B.V. All rights reserved.
1. Introduction
and synthons for linking 99mTc to targeting vectors [4]. The
challenge here is the general incompatibility of most organometal-
Metallic elements are a primary source of medical isotopes for
diagnostic and therapeutic nuclear medicine procedures. As an
example, approximately 80% of diagnostic scans utilize 99mTc due
to its nearly ideal nuclear properties, widespread availability and
low cost [1]. Other metals are playing increasingly important roles
in designing a new generation of targeted diagnostic (e.g. 64Cu and
89Zr) and therapeutic (e.g. 90Y and 177Lu) agents [2]. The creation of
the next generation of metal-based radiopharmaceuticals that can
seek out specific targets and that have optimal pharmacokinetic
properties requires the development of new ligands, bioconjuga-
tion strategies and radiolabeling reactions.
In the case of technetium, the preponderance of work used to
develop new radiopharmaceuticals to date has relied on classic
coordination chemistry in which a multi-dentate chelate is ap-
pended to a targeting vector [1,3]. An alternative approach is to
use organometallic chemistry to prepare unique architectures
lic reactions with the aqueous and dilute reaction conditions used
to prepare radiopharmaceuticals. Nonetheless, several groups have
shown that organometallic ligands such as cyclopentadiene can be
radiolabeled with 99mTc using both indirect and direct labeling
methods [5].
The application of organometallic radiochemistry is particularly
attractive for creating radiopharmaceuticals that can target specific
proteins in the central nervous system (CNS) and therefore be used
to characterize and diagnose neurological and psychological disor-
ders such as schizophrenia, Alzheimer’s disease and Parkinson’s
disease [6–12]. Cyclopentadiene (Cp) based radiometal complexes
for instance have been developed to target neuroreceptors
however they have shown low brain uptake and/or poor target
binding in vivo [13]. An alternative class of organometallic ligands
are carboranes which are known to form stable complexes with a
variety of metals in a manner analogous to Cp [14]. 99mTc-carbo-
rane complexes can be prepared in aqueous media and targeting
vectors can be incorporated at a carbon or boron atom using a
number of robust synthetic strategies [15]. Carborane-based
ligands are attractive candidates for imaging CNS targets because
Abbreviations: CNS, central nervous system; BBB, blood–brain barrier.
Corresponding author. Tel.: +1 905 525 9140x20182; fax: +1 905 522 7776.
E-mail address: valliant@mcmaster.ca (J.F. Valliant).
⇑
0020-1693/$ - see front matter Ó 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.ica.2012.03.017

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A.S. Louie et al. / Inorganica Chimica Acta 389 (2012) 159–167
the cluster is compact, relatively low molecular weight and lipo-
philic which increases the likelihood that derivatives can cross
the blood–brain barrier (BBB) [16–18].
Recently we reported that rhenacarborane-1-(2-methoxy-
phenyl)-piperazine (WAY) conjugates (Fig. 1) in which one of the
or AV600MHz spectrometer at ambient temperature. The chemical
shifts are reported in parts per million (ppm), with 1H NMR shifts
referenced to the residual proton signal of the deuterated solvent
and the 13C shifts referenced to the carbon signal of the solvent.
The peaks for 11B{1H} NMR spectra are reported relative to an
external standard of BF3ÁEt2O. Infrared spectra were acquired on
a Bio-Rad FTS-40 or Nicolet 510 Fourier Transform IR spectrometer
at ambient temperature. Samples were run neat on a KBr plate. A
Gallenkamp melting point apparatus was used to determine melt-
ing points. Reactions involving microwave heating were performed
on a Biotage Initiator 60 microwave reactor using crimp-sealed
Emry vials. Mass spectra were obtained from the McMaster
Regional Centre for Mass Spectrometry utilizing a Micromass Quat-
tro Ultima (LC-ESI/APCI Triple Quadrupole) mass spectrometer for
electrospray ionization (ES) mass spectrometry, a Micromass GC-
EI/CI Time of Flight mass spectrometer instrument for chemical
ionization (CI) and electron ionization (EI) spectra and a Micromass
Global Ultima (MALDI/CapLC-ESI Quadrupole Time of Flight) mass
spectrometer for high resolution mass spectra.
compounds (12a) showed high affinity for a-adrenergic receptors
[19]. During the preparation of 12a and related analogues we ob-
served, by NMR, a cage isomerization process for select rhenacar-
borane derivatives. Here we report a more detailed study of the
structure and reactivity of this interesting class of carborane li-
gands including X-ray structures of a series of closo- and nido-li-
gands and a unique rhenacarborane isomer. To complete the
study, the technetium-carborane complexes were prepared in
which differences in the chemistry between rhenium and techne-
tium were observed, and the distribution coefficients (logD values)
of the products determined.
2. Experimental
2.1. Reagents and general procedures
High performance liquid chromatography (HPLC) was per-
formed on an Agilent 1100 system (Quad Pump module G1311A,
Degasser G1322A, ALS G1313A, Colcom G1316A) interfaced to a
BioScan radioactivity detector (APIFC2-00507). A Varian Nucleosil
C18 100-5 (250 Â 4.6 mm) column was used with a flow rate of
0.5 or 1 mL/min. The wavelength of detection was set at 254 nm.
The following solvent gradient was employed (solvent A = acetoni-
trile (0.1% formic acid), solvent B = 20 mM ammonium acetate):
0–15 min, 65–100% A, 15–20 min 100% A.
Unless otherwise stated, all chemicals and reagents were pur-
chased and used as received from Sigma–Aldrich without further
purification. Decaborane was purchased and used as received from
Katchem Ltd. Compounds 9a, 10a and 12a [19] and
[Re(CO)3(H2O)3][Br] [20] were prepared according to literature
procedures.
Reactions were performed under an inert atmosphere unless
otherwise stated. All solvents were obtained from Caledon, and
either dried by a Pure-Solv Solvent Purification System (Innovative
Technology Inc.) or dried over calcium hydride (acetonitrile), so-
dium/benzophenone (THF) or sodium iodide (acetone) and dis-
tilled prior to use. Deuterated solvents for NMR samples were
purchased from Cambridge Isotope Laboratories. Reactions were
monitored using Alugram Sil G/UV254 thin-layer chromatography
(TLC) plates. Carborane-containing species were visualized with
0.2% PdCl2 in hydrochloric acid (3.0 M) which, upon heating, gave
dark brown spots. Column chromatography was accomplished
with Ultra Pure Silica Gel 60 (Silicycle). Automated normal and re-
verse-phase (C18) silica gel chromatography were performed on a
Biotage SP1 purification system operated at ambient temperature
using solvent gradients as specified.
2.3. Synthesis of 1-bromomethyl-closo-1,2-C2B10H11 (1)
Adapted from a procedure reported by Zakharkin et al. [21],
decaborane (2.7 g, 0.02 mol) was dissolved in acetonitrile (30 mL)
and heated for 1 h at reflux (82 °C). To the resultant light yellow
solution, propargyl bromide (80% wt in toluene, 3.7 mL, 0.03 mol)
was added dropwise with stirring. The reaction mixture was
heated at reflux for 5 days after which the solution was concen-
trated to dryness leaving an orange oil. The residue was dissolved
in diethyl ether (30 mL) and extracted with aqueous sodium
hydroxide (0.1 M, 3 Â 25 mL). The organic fraction was dried over
anhydrous sodium sulfate, filtered and concentrated under re-
duced pressure to a viscous oil. Silica gel (5 g) was added to the yel-
low residue which was then stirred with hexanes (100 mL) for 1 h,
after which the mixture was filtered and this process was repeated
twice more. The filtrate was concentrated under reduced pressure
to yield compound 1 as a white solid (3.1 g, 65%). TLC Rf (100%
2.2. Instrumentation
Nuclear Magnetic Resonance spectra (1H, 13C, 11B{1H}, 1H NOE
and 2D experiments) were recorded on either a Bruker DRX500
CO
CO
CO
Re
CO
OC
OC
Re
H
H
N
N
C
H
N
C
C
C
OMe
C
N
OMe
N
n
C
OMe
N
n = 1, 3
n = 3, 6
10a
9a
CO
H
CO
CO
OC
H
N
C
H
Re
OC
CO
C
O
N
C
H
Re
C
N
N
OMe
N
H
N
MeO
O
H
N
C
N
C
11
H
N
O
12a
12c
MeO
Fig. 1. Carborane and rhenacarborane-WAY targets.

A.S. Louie et al. / Inorganica Chimica Acta 389 (2012) 159–167
161
Table 1
X-ray crystal data for 3, 6 and 11.
Parameter
3
6
11
CCDC number
Empirical formula
Formula weight
Space group
a (Å)
850149
850150
850151
C14H28B10N2O
C16H32B10N2O
376.54
P2(1)/n
9.0066(2)
17.3586(3)
14.7293(2)
90
C18H35B9N3O2, 0.3(CH3OH), 0.3 (CH2Cl2), 0.3 (H2O)
348.48
P2(1)
11.5107(11)
7.1360(7)
24.391(2)
90
470.74
P2(1)/c
13.158(4)
21.799(6)
11.253(3)
90
b (Å)
c (Å)
a
(°)
b (°)
93.601(5)
90
1999.6(3)
4
90.9720(10)
90
2302.48(7)
4
108.040(5)
90
2302.48(7)
4
c
(°)
V (Å3)
Z
T (K)
173(2)
0.71073
1.158
295(2)
1.54178
1.086
173(2)
0.71073
1.019
k (Å)
Dcalc (g cmÀ3
)
l
(mmÀ1
)
0.063
0.439
0.112
F(000)
736
800
1002
R
Rw
0.0553
0.1408
0.0445
0.0533
0.0997
0.1632
hexanes) = 0.44; m.p. = 32 °C; 1H NMR (500 MHz, CDCl3): d 4.00 (s,
1H, CH), 3.96 (s, 2H, CH2); 13C{1H} NMR (125 MHz, CDCl3) d: 71.4,
61.1, 32.3; 11B{1H} NMR (160 MHz, CDCl3) d: À2.9, À5.5, À9.2,
2.6. Synthesis of 1-iodopropyl-closo-1,2-C2B10H11 (5)
Adapted from a procedure reported by Sogbein et al. [17], com-
pound 3 (0.25 g, 1.12 mmol) was dissolved in acetone (10 mL) and
combined with a solution of sodium iodide (0.27 g, 1.80 mmol) in
acetone (10 mL) and the reaction mixture heated at reflux (56 °C)
for 3 days. After cooling to room temperature, the heterogeneous
mixture was filtered and the residue was washed with diethyl ether
(25 mL). The filtrate was concentrated and the residue was re-dis-
solved in diethyl ether (50 mL) and extracted with 10% sodium thio-
sulfate (3 Â 25 mL). The organic fraction was dried over anhydrous
sodium sulfate, filtered and the solvent removed under reduced
pressure to yield 5 as a pale yellow solid (0.34 g, 96%). TLC Rf
(100% petroleum ether) = 0.22; m.p. = 53 °C; 1H NMR (500 MHz,
CDCl3): d 3.58 (s, 1H, CH), 3.13 (t, 2H, CH2, 3J = 6.5 Hz), 2.34 (m,
2H, CH2), 1.98 (m, 2H, CH2); 13C{1H} NMR (125 MHz, CDCl3) d:
61.7, 39.1, 32.5, 31.0, 3.6; 11B{1H} NMR (160 MHz, CDCl3) d: À2.7,
À11.0, À12.9, À13.4; IR (KBr, cmÀ1):
m 3067, 2594; HRMS (EI+)
m/z for C3H13B10Br: calculated: 238.1131, observed: 238.1125 [M+].
2.4. Synthesis of 1-[1-(2-methoxyphenyl)-4-methylpiperazine]-closo-
1,2-C2B10H11 (3)
Diisopropylethylamine (1.0 mL, 5.7 mmol) was added to a stir-
ring solution of compound 1 (1.0 g, 4.2 mmol) and 1-(2-methoxy-
phenyl)piperazine (2, 1.0 g, 5.2 mmol) in (30 mL). The reaction
mixture was heated at reflux for 24 h. Upon cooling, the resultant
suspension was filtered and the solvent was removed under re-
duced pressure. The product was purified by flash silica gel chro-
matography employing a gradient of 75–100% dichloromethane/
hexanes giving an off-white solid following rotary evaporation of
the solvent (0.4 g, 27%). Characterization data is consistent with
that for 3 reported previously and prepared by a different method
[19].
À6.1, À9.7, À12.1, À12.5, À13.5; IR (KBr, cmÀ1):
m 3058, 2600;
HRMS (EI+) m/z for C5H17B10I: calculated: 314.1306, observed:
314.1314 [M+].
2.7. Synthesis of 1-[1-(2-methoxyphenyl)-4-propylpiperazine]-closo-
C2B10H11 (6)
2.5. Synthesis of 1-chloropropyl-closo-1,2-C2B10H11 (4)
Diisopropylethylamine (0.10 mL, 0.57 mmol) and 1-(2-
methoxyphenyl)piperazine (1.5 g, 7.8 mmol) were combined in
THF (3 mL) and added to a stirred solution of compound 5
(0.11 g, 0.35 mmol) in THF (5 mL). The reaction mixture was stirred
for 24 h at 22 °C. The solvent was removed from the suspension
under reduced pressure to yield a white solid. Dichloromethane
(30 mL) was added and the homogeneous solution was extracted
with water (3 Â 20 mL); the aqueous fractions were combined
and the product was extracted with dichloromethane (2 Â
25 mL). The combined organic fractions were dried over anhydrous
sodium sulfate, filtered and concentrated under reduced pressure.
The product was purified by automated silica gel chromatography
employing a gradient of 0–2% methanol/dichloromethane giving a
beige solid (0.08 g, 60%). Characterization data is consistent with
data reported in the literature [19].
Adapted from a procedure reported by Zakharkin et al. [21],
decaborane (2.1 g, 0.02 mol) was dissolved in acetonitrile (25 mL)
and heated for 1 h at reflux (82 °C). To the resultant light yellow
solution, chloropentyne (2.5 mL, 0.02 mol) was added with stirring.
The reaction mixture was heated at reflux for 5 days after which
the solution was concentrated to dryness using a rotary evaporator
leaving an orange oil. The residue was dissolved in diethyl ether
(50 mL) and extracted with water (3 Â 30 mL). The organic fraction
was dried over anhydrous sodium sulfate, filtered and concen-
trated under reduced pressure. Silica gel (5 g) was added to the or-
ange oil which was then stirred with hexanes (100 mL) for 1 h,
after which the mixture was filtered and this process was repeated
twice more. The filtrate was concentrated under reduced pressure
to yield 5 as a white solid (0.3 g, 8%). TLC Rf (50% diethyl ether/hex-
anes) = 0.62; m.p. = 50 °C; 1H NMR (500 MHz, CDCl3): d 3.59 (s, 1H,
CH), 3.51 (t, 2H, CH2, J = 6.1 Hz), 2.39 (m, 2H, CH2), 1.97 (m, 2H,
CH2); 13C{1H} NMR (125 MHz, CDCl3) d: 74.3, 61.8, 43.4, 35.7,
32.0; 11B{1H} NMR (160 MHz, CDCl3) d: À1.8, À5.2, À8.8, À11.3,
2.8. Synthesis of {[Na][2,2,2-(CO)3-1-(C16H24N3O2)-2,1,8-closo-
ReC2B9H10]} (12c)
À11.7, À12.6; IR (KBr, cmÀ1):
m
3058, 2574; HRMS (EI+) m/z for
The synthesis of the mixture of 12a/c was performed as previ-
ously described [19]. Isolation of the minor isomer 12c was
C5H17B10Cl: calculated: 222.1949, observed: 222.1950 [M+].

162
A.S. Louie et al. / Inorganica Chimica Acta 389 (2012) 159–167
achieved using silica gel column chromatography and an eluent
consisting of 10% methanol/dichloromethane. Rf (10% methanol/
dichloromethane) = 0.76. 1H NMR (600 MHz, CD3CN) d: 7.05 (m,
1H, Ar–H), 6.94 (m, 3H, Ar–H), 6.12 (s, 1H, NH), 3.83 (s, 3H,
OCH3), 3.11 (m, 6H, NCH2, CH2), 3.00 (m, 6H, NCH2, CH2), 2.61 (s,
1H, CH), 1.69 (m, 2H, CH2), 1.49 (m, 2H, CH2); 13C NMR
(150 MHz, CD3CN) d: 199.8, 172.6, 153.4, 140.5, 125.0, 122.0,
119.5, 113.0, 57.3, 56.1, 53.9, 48.4, 38.3, 37.3, 27.8, 21.2; 11B{1H}
NMR (160 MHz, CD3CN) d: À6.9, À10.6, À13.1, À17.5, À18.8,
2.11. LogD measurements
The logD values of compounds were determined by the shake
flask method between n-octanol and phosphate buffer (0.02 M,
pH 7.4) [28]. Approximately 222 kBq (6 lCi, 200 lL) of the techne-
tium complex (5–10% ethanol/saline) was used in each experiment
and the partition coefficient was determined by taking the loga-
rithm of the ratio of activities (n-octanol/buffer).
À19.6; IR (KBr, cmÀ1):
m 3426, 2917, 2849, 2560, 2003, 1895; HRMS
3. Results and discussion
(ESÀ) m/z for C21H34B9N3O5Re: calculated: 694.2894, observed
694.2951 [M+].
3.1. Synthesis and characterization of carborane derivatives
We recently reported the syntheses of rhenacarborane com-
plexes 9a, 10a and 12a (Fig. 1) which were screened for their affin-
ity towards a series of neuroreceptors and transporters including
serotonin, adrenergic and sigma receptors. Complex 12a showed
high affinity toward 5-HT7 serotonergic receptor (40 nM), and
adrenoceptors a1A (17 nM), a1D (21 nM) and a2C (39 nM) [19].
While there are a number of PET probes (11C or 18F) reported for
imaging adrenergic receptors, this was the first reported organo-
metallic complex that demonstrated high binding to the target.
In the initial publication, the closo-carboranes 3 and 6 were pre-
pared using the classic alkyne insertion reaction where the alkynyl
precursors were treated with decaborane in the presence of an io-
nic liquid (Scheme 1) [19]. This procedure required multiple puri-
fication procedures to isolate 3 and 6, consequently an alternative
synthetic strategy was developed whereby carboranes bearing a
reactive halo-alkyl unit (Cl, Br and I) were generated and subse-
quently treated with 1-(2-methoxyphenyl)piperazine 2 (Scheme
2). Carboranes (bromo-1, chloro-4) were prepared using either
propargyl bromine or chloropentyne in acetonitrile. The iodo-car-
borane derivative 5 was generated from the chloro-carborane 4
in 96% yield using a Finkelstein reaction and sodium iodide
(Scheme 2b). The conversion to the iodide can be readily moni-
tored using 1H NMR where the methylene group at 3.51 ppm for
4 shifted to 3.13 ppm upon substitution.
2.9. X-ray analyses
Data was collected at 100 K on a Bruker APEX2 diffractometer
equipped with CCD area detector using a graphite monochromator,
Mo K
D8 diffractometer equipped with a CCD area detector using fine fo-
cused parallel mirrors, Cu K radiation and phi and omega scans.
a radiation and phi and omega scans or at 295 K on a Bruker
a
The SMART suite was used for data collection and SAINT was used
for data reduction; data was scaled using SADABS with both face-in-
dexed absorption correction as well as a correction using redun-
dant data [22–24]. Data was collected in omega- and phi-scans
and integrated as a two component twin using the program SAINT
.
An empirical absorption correction using the program TWINABS
was applied. The structure was then solved by direct methods
and refined by full matrix least-squares refinement on F2 using
the Bruker SHELXTL program library [25]. Two disordered molecules
of CH2Cl2 were removed from 12c using SQUEEZE [26]. In 11, atom N2
is protonated, as evidenced by the slightly longer N–C bond within
the ring [27] which explains why there is no residual counterion in
the structure. Further details can be found in the Supplementary
data.
2.10. Radiochemistry with technetium-99m
Synthesis of carborane 3 was achieved via substitution reaction
of closo-carborane 1 with 1-(2-methoxyphenyl)piperazine 2 to
yield the desired product in 27% yield (Scheme 2a). No significant
increase in yield was observed for the preparation of 3 using the
halo-alkyl carborane instead of the insertion reaction however
the substitution reaction produced fewer by-products eliminating
the need for multiple purification procedures. The one-pot in situ
Caution: 99mTc is a
c-emitter (Ec = 140 keV, t1/2 = 6 h) and
should only be used in a licensed and appropriately shielded facil-
ity. Pertechnetate [99mTcO4]À was obtained from a 99Mo–99mTc
generator (Lantheus Medical Imaging) in saline (0.9% NaCl).
[
99mTc(CO)3(H2O)3]+, 9b, 9c, 10b, 12b and 12d were prepared
according to literature procedures [19]. Reactions involving micro-
wave heating were performed on a Biotage Initiator 8 microwave
reactor using crimp-sealed vials. Solid phase extraction cartridges
(C18) obtained from Waters were used following pre-treatment
with water (10 mL), methanol or ethanol (10 mL), a second wash
with water (10 mL) and HCl (10 mM, 10 mL). A Capintec dose cal-
ibrator was used to determine the activity of samples containing
technetium-99m (>300 kBq). A Perkin Elmer 1470 Wizard gamma
counter was used to measure lower amounts of radioactivity
(<300 kBq) for the lipophilicity measurements.
generation of
5 from 4 in the presence of 1-(2-methoxy-
phenyl)piperazine led to a 25% yield of 6. A two step synthesis in
which the chloro-carborane 4 was converted to 5, followed by
the isolation of the iodo-carborane and subsequent reaction with
the arylpiperazine 2 generated compound 6 with the highest yield
(60%) (Scheme 2b). The yields and purification of 6 from the
substitution reaction are significantly improved relative to the al-
kyne insertion reaction using an ionic liquid (13%) even with the
increase in the number of steps. When chloro-carborane 4 was
H
N
N
[BMIM][Cl]
C
B10H12L2
C
N
OMe
N
n
OMe
n
n = 1, 3
n = 3, 6
L = ACN
n = 1, 3
Scheme 1. Synthesis of compounds 3 and 6 using an alkyne insertion reaction.

A.S. Louie et al. / Inorganica Chimica Acta 389 (2012) 159–167
163
(a)
(b)
H
H
H
N
N
C
C
C
2 =
HN
2, DIPEA
THF
C
C
N
Br
OMe
OMe
N
3
1
H
C
NaI
H
C
C
2, DIPEA
THF
C
Cl
I
C
N
OMe
acetone
4
5
6
Scheme 2. Alternative synthesis of 3 and 6 via substitution reactions.
treated directly with 1-(2-methoxyphenyl)piperazine compound 6
was isolated in only 15% yield.
Multi-NMR and MS characterization of compounds 3 and 6
matched the data obtained using the alkyne insertion route [19]
and there was no evidence of nido-carborane formation which
can occur in the presence of secondary amines [29]. X-ray quality
single crystals of the products were obtained for the first time by
slow evaporation of concentrated dichloromethane solutions (Figs.
2 and 3, Table 1). Compound 3 crystallized with two independent
molecules in the lattice. The C–C bond lengths are 1.62 and 1.65 Å
and the cage B–B bond distances ranges from 1.75 to 1.81 Å. Com-
pound 6 has similar C–C cage (1.65 Å) and average B–B bond dis-
tances (1.76 Å). Both of these structures have comparable data to
other mono-substituted closo-carborane compounds reported in
the literature (average C–C and B–B bond lengths are typically
around 1.65 and 1.77 Å, respectively) [30].
Fig. 2. X-ray crystal structure of 3 (showing 50% probability thermal ellipsoids;
hydrogen atoms omitted for clarity).
The X-ray crystal structure of the nido-carborane ligand 11 [19],
which contains an amide bond between the cluster and the target-
ing vector was also obtained. The structure confirms that the two
cage carbons are adjacent to each other (Fig. 4, Table 1) which is
important as this cluster isomerizes upon reaction with rhenium
and technetium (vide infra). The C–C bond length in the carborane
cage was 1.67 Å which is similar to the closo-carborane 3 (1.65 Å)
and is somewhat longer than other reported nido-carborane deriv-
atives (1.55 Å) [31–35]. The average B–B cage bond length of 11 is
1.77 Å which falls within the reported B–B bond lengths of other
nido-carborane analogues [31–36]. A counter ion was not present
in the crystal lattice of 11 because one of the piperazine nitrogen
atoms (N2) is protonated.
Fig. 3. X-ray crystal structure of 6 showing 50% probability thermal ellipsoids;
hydrogen atoms omitted for clarity.
3.2. Preparation of rhenacarborane complexes
The preparation of the rhenacarborane complexes was achieved
by microwave heating the nido-forms of the carborane ligands 3, 6
and 11 with [Re(CO)3(H2O)3]Br (Scheme 3) [19]. Single quality
crystals of complex 9a were obtained by slow evaporation from a
chloroform solution and the structure determined for the first time
(Fig. 5, Table 2). Upon the refinement of the data, the 3,1,2 isomer
of the rhenium-carborane, where the two cage carbon atoms are
adjacent to one another in the C2B3 face, was not observed. Instead,
the carbon atom bearing the arylpiperazine group migrated out of
the five-membered ring bound to the metal atom generating a
2,1,8-configuration. Isomerization of this nature for metal-carbo-
rane complexes other than rhenium [16] (e.g. Pt, Ni, Rh, Ir) has
been observed [37–40,45–47]. One of the piperazine nitrogen
atoms in 9a is protonated which is supported by the slightly longer
N–C bond within the ring [27]. The average Re–B bond distance of
9a in the metallocarborane is 2.31 Å which is similar to the Re–C
cage bond distance of 2.32 Å. The metal–carbon bond distance is
comparable to the average bond length (2.31 Å) observed for the
Fig. 4. X-ray crystal structure of 11 showing 50% probability thermal ellipsoids;
hydrogen atoms omitted for clarity.

164
A.S. Louie et al. / Inorganica Chimica Acta 389 (2012) 159–167
CO
M
CO
OC
H
C
(a)
N
C
OMe
N
H
H
N
H
N
N
M = Re, 9a
N
[M(CO)3(H2O)3]+
M = Re, 99mTc
C
C
NaF
M = 99mTc, 9b
C
C
OMe
OMe
n
n
CO
OC
CO
M
n = 1, 7
n = 3, 8
n = 1, 3
n = 3, 6
H
N
C
C
N
OMe
M = Re, 10a
M = 99mTc, 10b
CO
CO
OC
(b)
M
H
C
H
N
H
C
H
N
N
C
C
H
[M(CO)3(H2O)3]+
M = Re, 99mTc
N
O
N
N
O
M = Re, 12a
M = 99mTc, 12b
MeO
11
MeO
CO
M
OC
CO
C
O
N
N
OMe
N
H
M = Re, 12c
M = 99mTc, 12d
C
H
Scheme 3. Synthesis of metallocarborane complexes.
Table 2
X-ray crystal data for 9a and 12c.
Parameter
9a
791174
18H30B9Cl2N2O4Re
12c
CCDC number
Empirical formula
Formula weight
Space group
a (Å)
850152
C21C35B9C14N3O5Re 2(CH2Cl2)
847.85
Pbcn
C
692.83
ꢀ
P1
10.4983(3)
11.7176(4)
12.7395(4)
117.134(2)
98.936(2)
99.964(2)
1323.67(7)
2
10.3572(8)
19.9585(15)
32.252(3)
90
90
90
b (Å)
c (Å)
a
(°)
b (°)
c
(°)
V (Å3)
Z
6666.9(9)
8
T (K)
100(2)
0.71073
1.738
173(2)
0.71073
1.689
k (Å)
Fig. 5. X-ray structure of 9a showing 50% probability thermal ellipsoids; hydrogen
atoms omitted for clarity.
Dcalc (g cmÀ3
)
l
(mmÀ1
)
4.821
4.004
F(000)
676
3348
R
Rw
0.0512
0.0616
0.0355
0.0450
analogous cyclopentadienyl-WAY rhenium complex (CpRe(CO)3-
WAY) reported by Alberto and co-workers [40]. To confirm that
the bulk material exists as the 2,1,8-isomer, a 1H NOE experiment
was performed by irradiation of the carborane CH proton which
did not cause enhancement of the proton resonances in the ali-
phatic spacer group. This result indicated that the carborane CH
and the targeting groups are not in close proximity, which is con-
sistent with the X-ray data and the formation of a 2,1,8 isomer.
A variable temperature experiment in the microwave reactor
was undertaken to better understand the observed isomerization
and to determine if the ligand isomerizes prior to or during com-
plexation, or if the 3,1,2-isomer forms first followed by isomeriza-
tion to the 2,1,8-form. A series of reactions were conducted in
which 7 was combined with [Re(CO)3(H2O)3]Br over a range of
temperatures from 100 to 200 °C at a fixed reaction time of
10 min. The products were then analyzed by 1H NMR spectroscopy
where the results indicated that complex formation begins at tem-
peratures greater than 150 °C and there was no evidence of isom-
erization of the free nido-ligand prior to complexation. There was
also no evidence for the formation of the 3,1,2-rhenium carborane
complex prior to isomerization to the 2,1,8-configuration. The
isomerization of 9a is likely due to the steric bulk of the arylpiper-
azine unit, which is in close proximity to the binding face of the
cluster providing an impetus for the carborane cage to isomerize

A.S. Louie et al. / Inorganica Chimica Acta 389 (2012) 159–167
165
substituents (2.27–2.35 Å) [38]. The average B–B bond length for
12c is 1.78 Å which is the same as 12a and 9a as well as other
mono-substituted 2,1,8-rhenacarboranes (1.80 Å) [30]. One of the
nitrogen atoms (N2) is protonated as was observed for 9a and 11.
The 1H NMR spectrum of 12c shows resonances at 6.12 and
2.61 ppm for the amide proton and the unsubstituted carborane
proton, respectively; while the corresponding resonances for 12a
can be found at 6.53 and 1.86 ppm [19]. Prior to complexation,
the unsubstituted carborane CH of 11 displayed a signal in the 1H
NMR at 2.53 ppm, which moved upfield in 12a while for 12c there
was a small downfield shift providing a convenient means of differ-
entiating between the two isomers. The 11B{1H} NMR spectrum
showed modest changes between the two isomers in terms of
chemical shifts (12a: À5.8 to À19.9 ppm [19]; 12c: À6.9 to
À19.6 ppm) and intensities of the peaks.
For 12a/c, unlike in the case of 9a, the steric bulk of the arylpip-
erazine group is likely not driving the isomerization of the carbo-
rane cage. The amido spacer is similar in size to that found in 10a
where no cage isomerization was observed [19]. Electron with-
drawing substituents (like the amide group), as previously men-
tioned, lower the energy barrier to isomerization in other
rhenacarborane complexes [30] and is likely the driving force here.
Isomerization that leads to the movement of the carbon atom bear-
ing the substituent is favoured since it also reduces steric interac-
tions between the substituents and the metal-tricarbonyl fragment.
3.3. Preparation of the 99mTc-carborane complexes
Fig. 6. X-ray crystal structure of 12c showing 50 % probability thermal ellipsoids;
hydrogen atoms omitted for clarity.
Having fully characterized the ligands and metal complexes, the
next step was to label the ligands with 99mTc, and compare the rel-
ative amounts of the isomers to see if there were differences be-
[30]. This is consistent with our previous work on aryl substituted
carboranes which displayed effectively concomitant coordination
of [Re(CO)3]+ and isomerisation [16,30]. We have also observed
that electron withdrawing groups including protonated benzylic
pyridine derivatives also promote facile isomerization [30]. Given
that the product contained a protonated piperazine ring one meth-
ylene spacer away from the cluster, one cannot rule out electronic
influences as well.
tween the congeners.
A series of reactions were conducted
between [99mTc(CO)3(H2O)3]+ and nido-carborane 7 between 100
and 195 °C for a fixed time (5 min) and the reaction mixture ana-
lyzed by HPLC to compare the retention times of the 99mTc-com-
plex (gamma detection) and the rhenium reference standards
(UV detection). At temperatures greater than 190 °C, only one com-
plex was observed 9b (tR = 15.7 min) and the peak in the radio-
HPLC correlated with the rhenacarborane 9a (tR = 15.0 min) in
the UV chromatogram. For reaction temperatures between 140
and 180 °C, two 99mTc-complexes were observed: 9b and a species
with a shorter retention time (tR = 14.9 min); at temperatures
<140 °C, only the tR = 14.9 min species was present. These observa-
tions suggest the formation of the 3,1,2-99mTc-carborane complex
9c at lower temperatures followed by the conversion to the 2,1,8
isomer 9b as the temperature was increased (Scheme 4). This
hypothesis was supported by firstly preparing 9c (tR = 14.9 min)
and then observing by HPLC its conversion to 9b by heating at
195 °C for 5 min. Complex 9c was isolated by solid phase extrac-
tion (SPE) and HPLC where the decay corrected radiochemical yield
was 21%. The labeling reactions for 8 and 11 produced single peaks
in which the isomers observed were consistent with the reactions
involving rhenium [19].
The cage configuration of rhenacarborane 10a, which has a
longer spacer group between the cluster and the ligand, was eval-
uated by 1H NOE experiments. Irradiation of the cage CH proton
caused a change in the signal associated with the aliphatic spacer
group and some enhancement of the proton resonances of the
piperazine ring indicating that the unsubstituted carborane CH is
in close proximity to the targeting vector and that the relative posi-
tions of the cage carbon atoms of the parent cluster were retained
in the product. The extended linker in compound 6 eliminated the
steric and electronic influences of the piperazine ring thereby
increasing the barrier to isomerization. Unfortunately, repeated at-
tempts to grow X-ray quality crystals of 10a were not successful.
Compound 11 was treated with [Re(CO)3(H2O)3]+ in a micro-
wave reactor (Scheme 3b) where, following work up, TLC indicated
the formation of two major products which were present in a ratio
of 3:1 based on integration of the 1H NMR spectrum of the reaction
mixture. Using preparative TLC, the products were isolated and
ESMS indicated the two compounds had the same m/z values and
isotope distribution patterns. The major product was 12a which
had been prepared and characterized previously and was the com-
In the case of 7 the temperature threshold for complexation and
isomerization for 99mTc do not match those seen for Re. Compound
7 showed simultaneous complexation and cage isomerization with
Re where the presence of the 3,1,2 isomer was not observed at low-
er reaction temperatures. Other carborane derivatives have been
reported where the complexation temperatures for preparing the
3,1,2- and 2,1,8-complexes for Re and 99mTc are also different
[41]. The unique isomerization behavior for the carborane ligands
is most likely due to the differences in energy barriers to isomeri-
zation caused by the steric bulk and specific nature of the linker
(amide versus alkyl) between the carborane and the substituents.
With respect to differences observed between Re and 99mTc for 7,
this can be attributed to changes in redox potentials for the two
pound which exhibited high affinity for
a-adrenergic receptors
[19]. The X-ray structure of the minor isomer 12c which was hith-
erto unknown, was obtained from crystals grown by slow evapora-
tion of a methanol and dichloromethane solution (Fig. 6). The Re–C
bond length of 12c is 2.32 Å which is comparable to that in 12a
(2.33 Å). The Re–B bond lengths range from 2.29 to 2.36 Å for
complex 12c which are similar to Re–B bond lengths of 12a
(2.28–2.34 Å) and the bond lengths of a phenol substituted rhe-
nium carborane complex with an analogous orientation of the

166
A.S. Louie et al. / Inorganica Chimica Acta 389 (2012) 159–167
CO
CO
OC
99mTc
CO
OC
CO
H
99mTc
H
H
H
N
N
N
C
C
[
99mTc(CO)3(OH2)3]+
< 140 oC
C
C
OMe
C
OMe
N
N
C
OMe
N
> 190 oC
7
9c
Scheme 4. Radiolabelling and isomerization of carboranes.
9b
metals [41] where oxidation of the metal may be a key step in rear-
rangement of the cage; a hypothesis that is currently being tested.
Funding was provided for A.S.L. by the Province of Ontario (OGS-
ST), NSERC and The Department of Chemistry at McMaster
University.
3.4. Lipophilicity measurements
Appendix A. Supplementary material
Lipophilicity (logP) measurements are a fundamental physico-
chemical parameter used to evaluate new neurological imaging
agents [28]. Lipophilicity is used to predict the ability to deliver
the radiotracer to the desired organ (e.g. cross the blood–brain bar-
rier (BBB)) and to anticipate the rate of clearance from non-target
tissues [42]. In order to gauge the ability of the 99mTc-complexes to
cross the BBB and be potential CNS-targeted agents, the lipophilic-
ity values were measured. For an agent to diffuse through the BBB,
CCDC 791174, 850149, 850150, 850151 and 850152 contain the
supplementary crystallographic data for this paper. These data can
be obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif. Supplemen-
tary data associated with this article can be found, in the online
version, at http://dx.doi.org/10.1016/j.ica.2012.03.017.
a
99mTc complex should partition between n-octanol and water to
References
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