Synthesis and in vivo evaluation of 11C-labeled (1,7-dicarba-closo-dodecaboran-1-yl)-N-{[(2S)-1-ethylpyrrolidin-2-yl]methyl} amide

Article abstract of DOI:10.1002/jlcr.3159

Boron clusters, and especially dicarba-closo-dodecaboranes, can be used as hydrophobic pharmacophores in the design of new drugs and radiotracers because of their hydrophobic character, spherical structure, and excellent chemical and photochemical stability. In the present paper, the synthesis and in vivo evaluation of ¹¹C-labeled (1,7-dicarba-closo-dodecaboran-1-yl)-N- {[(2S)-1-ethylpyrrolidin-2-yl]methyl}amide, an analog of the D₂ receptor ligand [¹¹C]raclopride, is described. The radiosynthesis was approached by reaction of the demethylated precursor with [¹¹C] CH₃I in basic media; moderate radiochemical yields (18.2 ± 2.8%, decay corrected), and excellent radiochemical purities (>98%) were obtained in overall synthesis time of ~50 min. In vivo assays showed a biodistribution pattern with significant uptake in liver, kidneys and lungs at short times (t = 4 min) after administration and increasing accumulation in bladder at longer times (t ≥ 14.5 min). Although brain positron emission tomography scans showed good blood brain barrier penetration, the high unspecific uptake observed in different brain regions impedes its applicability as D₂ receptor ligand.

Full text of DOI:10.1002/jlcr.3159

Special Issue Article
Received 10 July 2013,
Accepted 29 October 2013
Published online 5 December 2013 in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/jlcr.3159
1
1
Synthesis and in vivo evaluation of C-labeled
1,7-dicarba-closo-dodecaboran-1-yl)-N-{[(2S)-
(
†
1
-ethylpyrrolidin-2-yl]methyl}amide
a
a
a
Vanessa Gómez-Vallejo, Naiara Vázquez, Kiran Babu Gona,
a
a
b
Maria Puigivila, Mikel González, Eneko San Sebastián,
c
a
Abraham Martin, and Jordi Llop *
Boron clusters, and especially dicarba-closo-dodecaboranes, can be used as hydrophobic pharmacophores in the design of
new drugs and radiotracers because of their hydrophobic character, spherical structure, and excellent chemical and
1
1
photochemical stability. In the present paper, the synthesis and in vivo evaluation of C-labeled (1,7-dicarba-closo-
1
1
dodecaboran-1-yl)-N-{[(2S)-1-ethylpyrrolidin-2-yl]methyl}amide, an analog of the D2 receptor ligand [ C]raclopride, is
1
1
3
described. The radiosynthesis was approached by reaction of the demethylated precursor with [ C]CH I in basic media;
moderate radiochemical yields (18.2 ± 2.8%, decay corrected), and excellent radiochemical purities (>98%) were obtained
in overall synthesis time of ~50 min. In vivo assays showed a biodistribution pattern with significant uptake in liver, kidneys
and lungs at short times (t = 4 min) after administration and increasing accumulation in bladder at longer times (t ≥ 14.5 min).
Although brain positron emission tomography scans showed good blood brain barrier penetration, the high unspecific
uptake observed in different brain regions impedes its applicability as D receptor ligand. Copyright © 2013 John Wiley &
2
Sons, Ltd.
Keywords: carbon-11; raclopride; PET; dopamine; receptor; dicarba-closo-dodecaboranes
Introduction
the hydrophobic structure of various biologically active molecules,
because both their spherical structure and their hydrophobic
Positron emission tomography (PET) is a non-invasive in vivo
imaging technique, which produces three-dimensional images
of functional processes in living organisms after administration
of a radiotracer. Among all positron emitters, carbon-11 (half-life
of 20.4 min and maximum positron energy of 960.5 KeV) is one of
the most interesting ones because it can be produced in
relatively high yields in commercially available cyclotrons. It
can be easily introduced in biomolecules; its decay mode is close
to 100% positron emission, and its stable isotope is present in al1l
organic molecules. PET has been used for the early diagnosis,
surface could interact with hydrophobic residues of the ligand
12,13
binding site of receptors.
Moreover, carboranes have excellent
thermal and photochemical stability in the ultraviolet (UV)-visible
range and are chemically versatile molecules. On the basis of
the approach of Endo et al., we have recently reported new
analogs of raclopride by introducing different carborane clusters
acting as hydrophobic pharmacophores using two different
14,15
synthetic pathways.
In the present paper, we report the
11
radiosynthesis of an analog of [ C]raclopride incorporating a
,7-dicarba-closo-dodecaborane unit [[ C]-1, Figure 1(b)] and its
11
1
2
evaluation of response to treatment, determination of
mechanistic aspects of biological and pathological processes,
evaluation as a potential D receptor marker in vivo.
2
3
and assessment of pharmacokinetic and pharmacodynamic
properties of new drugs. In this context, new radiotracers with
improved properties, for example, higher affinity and specificity
4
*Correspondence to: Jordi Llop, Radiochemistry Department, CIC-BiomaGUNE,
Pº Miramón 182, Parque Tecnológico San Sebastián, 20009 San Sebastián,
Guipúzcoa, Spain.
for a selected target, slower metabolism, or good penetration E-mail: jllop@cicbiomagune.es
of blood brain barrier are becoming more and more demanded
by the scientific community.
During the last decades, there has been an increasing interest
a
Radiochemistry Department, Molecular Imaging Unit, CIC biomaGUNE; Parque
Tecnológico de Miramón, San Sebastián, Guipúzcoa, Spain
b
in the development of radioligands for central D
2
receptors,
Image Analytics Department, Molecular Imaging Unit, CIC biomaGUNE; Parque
Tecnológico de Miramón, San Sebastián, Guipúzcoa, Spain
which are G-protein coupled receptors implicated in many
5
6
neurological processes, including motivation, cognition,
c
Molecular Imaging Unit, CIC biomaGUNE; Parque Tecnológico de Miramón, San
7
8
9
memory, learning, and fine motor control. Some of them Sebastián, Guipúzcoa, Spain
e.g., [ C]raclopride, Figure 1(a)] have been widely applied both
in preclinical and in clinical studies.
Endo and co-workers have reported that 1,2- and 1,7-dicarba-
1
1
[
†
1
0
11
This article is published in the Journal of Labelled Compounds and
Radiopharmaceuticals as a special issue on ‘Current Developments in PET and
SPECT Imaging’, edited by Jonathan R. Dilwoth, University of Oxford and Sofia I.
closo-dodecaborane (o-carborane and m-carborane) can mimic Pascu, University of Bath
J. Label Compd. Radiopharm 2014, 57 209–214
Copyright © 2013 John Wiley & Sons, Ltd.

V. Gómez-Vallejo et al.
those experiments devoted to the optimization of synthetic conditions,
the crude reaction mixture was collected in a vial, and radiochemical
conversion (RCC) values were calculated from chromatographic profiles
obtained under the same conditions.
Identification of the desired radiotracer was carried out by HPLC-MS
performed on the purified fraction after complete decay, using an
AQUITY UPLC separation module coupled to a LCT TOF Premier XE mass
spectrometer (Waters, Manchester, UK). An Acquity BEH C18 column
1
1
11
Figure 1. Chemical structure of (a) [ C]raclopride and (b) C-labeled (1,7-
dicarba-closo-dodecaboran-1-yl)-N-{[(2S)-1-ethylpyrrolidin-2-yl]methyl}amide
(
1.7 μm, 5 mm, 2.1 mm) was used as stationary phase. The elution buffers
1
1
(
[
C]-1). stands for BH, and ● stands for C.
were MEOH (A) and 0.1% formic acid aqueous solution (B). The column
was eluted with a linear gradient: t = 0 min, 95% B; t = 3 min, 1% B; t = 9
min, 1% B; and t = 10 min, 95%B. Total run was 10 min; injection volume
was 5 μL, and the flow rate was 600 μL/min. The detection was carried
out in positive ion mode, monitoring the most abundant isotope peaks
Experimental section
1
1
from the mass spectra. Compound [ C]-1 was detected as a protonated
species (m/z = 286.3) with retention time = 4.35 min.
General
Water and acetonitrile (MeCN, HPLC grade) were obtained from
Panreac Química (Madrid, Spain). C-18 Light Sep-Pak® cartridges were In vivo studies
obtained from Waters and were pre-conditioned, sequentially, with
Male rats weighting 275–300 g (Sprague–Dawley, 9 weeks, Harlan, Udine,
ethanol (5 mL) and water (5 mL). All other chemicals and solvents were
Analytical Grade purity and purchased from Sigma-Aldrich, unless
otherwise specified.
Italy) were used to perform PET studies. The animals were maintained
and handled in accordance with the Guidelines for Accommodation
and Care of Animals (European Convention for the Protection of
Vertebrate Animals Used for Experimental and Other Scientific Purposes)
and internal guidelines. PET studies were performed using an
Radiochemistry
eXploreVista-CT small animal PET-CT system (GE Healthcare). During the
3 C
I was carried out using a TRACERlab FX Pro PET studies, rats were kept normothermic using a heating blanket
11
1
1
The synthesis of [ C]CH
synthesis module (GE Healthcare). [ C]CH
an IBA Cyclone 18/9 cyclotron by irradiation (target current = 22 μA, submitted to brain scans, and three animals were subjected to whole
integrated current = 2 μAh) of a N /H
4
was directly generated in
(
Homeothermic Blanket Control Unit; Bruker). Three animals were
2
2
gas mixture with 18 MeV protons. body (WB) scans to assess the biodistribution pattern. In all cases,
The radioactive gas was trapped in Carbosphere 60/80 (Alltech
anesthesia was induced with 3% isoflurane and maintained by 1.5–2%
Associates, Inc.) at À140°C, desorbed by heating at 80°C and allowed to
of isoflurane in 100% O . The tail vein was catheterized with a 24-gauge
catheter for intravenous administration of [ C]-1 (12 ± 2.4 MBq, 300 μL),
2
11
11
react with iodine at 720°C to form [ C]CH
3
I in a gas circulating process.
1
1
TM
[
C]CH
3
I was selectively retained in a trap containing Porapak Q (50– which was injected concomitantly with the start of a PET dynamic
8
0 mesh, Waters Corporation) at room temperature, while unreacted acquisition.
1
1
TM
[
C]CH
4
was recirculated. After 8–9 cycles, the Porapak Q trap was
For brain scans, dynamic images were acquired (14 frames: 6 × 100 s,
11
heated at 190°C, and [ C]CH
3
I was distilled under continuous helium 4 × 4.5 min, and 4 × 8 min) in the 400–700 keV energetic window, with a
flow at 20 mL/min for 2.5 min. The gas stream was passed through a trap
total acquisition time of 1 h; for WB scans, the same frames were defined,
containing phosphorous pentoxide and Ascarite II® (20–30 mesh) before but four beds were acquired at each frame. After each PET scan, CT
TM
being introduced in the reaction loop (AutoLoop system, Bioscan Inc.) acquisitions were also performed (140 μA intensity and 40 kV voltage),
pre-charged with a solution of (1,7-dicarba-closo-dodecaboran-1-yl)-N-
providing anatomical information of each animal as well as the
in attenuation map for the later image reconstruction. Dynamic acquisitions
{[(2S)-pyrrolidin-2-yl]methyl}amide
(trifluoroacetate
salt)
dimethylformamide (DMF, 100 μL) and triethylamine (10 μL). After
were reconstructed, decay and CT-based attenuation corrected, with
1
1
complete trapping of [ C]CH
3
I, the reaction was allowed to occur for filtered back projection using a Ramp filter with a cut off frequency of
6
[
min at room temperature. For those experiments performed with 1 Hz.
1
1
11
C]CH
before entering the reaction loop, through a trap filled with 150– image analysis software (PMOD Technologies Ltd, Zürich, Switzerland).
00 mg of silver triflate fixed on Carbowax® 1500 80/100 (Grace Davison For brain scans, Regions of Interests (ROIs) were automatically generated
Discovery Science) in an online flowthrough process at 180°C under
3 3
OTf, [ C]CH I synthesized as described previously was passed,
Positron emission tomography images were analyzed using PMOD
2
by using a magnetic resonance imaging rat brain atlas provided by the
continuous helium flow (20 mL/min). After reaction in the loop, the software. Subsequently, PET images were co-registered to the anatomical
16
TM
1
7
crude was purified by HPLC (stationary phase: Supelcosil LC-ABZ + C18
data of the atlas by using the skull orientation provided by the CT
column, 250 × 10 mm, 5 μm; mobile phase: water/MeCN 10/90; flow image of the same animal, and ROIs were automatically applied. Specific
rate = 5 mL/min), and the desired fraction (retention time = 20–21 min, brain regions such as the striatum and cerebellum were considered. For
radiometric and UV detection) was collected and reformulated using
the TRACERlab FX Pro synthesis module by diluting with water reference. In both cases, time activity curves were derived for each ROI as
20 mL), trapping in a C-18 cartridge, rinsing with water, elution with
WB scans, ROIs were manually drawn using the CT images as anatomical
C
(
percent of injected dose per gram of tissue.
ethanol (1 mL), further elution with physiological saline solution (2 mL),
and final filtration through 0.22 μm filter (Millex®-GS, Millipore).
The amount of radioactivity of the final radiotracer was measured in a
dose calibrator (PETDOSE HC, Comecer), and a sample was submitted to Results and discussion
quality control. The radiochemical purity was determined by HPLC, using
Radiochemistry
an Agilent 1200 Series HPLC system with a multiple wavelength UV
detector (λ = 254 nm) and a radiometric detector (Raytest). A RP-C18
column (Eclipse XDB C18, 4.6 × 150 mm, 5 μm particle size) was used as
stationary phase and water/MeCN 25/75 as a mobile phase (retention
time = 11 min). Specific activity was estimated based on historical specific
11
The radiosynthesis of C-labeled (1,7-dicarba-closo-dodecaboran-
11
1-yl)-N-{[(2S)-1-ethylpyrrolidin-2-yl]methyl}amide ([ C]-1) was
approached by N-methylation of the corresponding desmethyl
activity values obtained using the same synthetic configuration, with the precursor, which was prepared following our previously reported
14
corresponding decay correction according to total preparation time. For method (Scheme 1) ; briefly: m-carborane was converted into its
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Copyright © 2013 John Wiley & Sons, Ltd.
J. Label Compd. Radiopharm 2014, 57 209–214

V. Gómez-Vallejo et al.
1
1
Scheme 1. Radiosynthesis of C-labeled (1,7-dicarba-closo-dodecaboran-1-yl)-N-{[(2S)-1-ethylpyrrolidin-2-yl]methyl}amide and its desmethyl precursor. Reagents: (i) n-
1
1
BuLi, ether, CO
2
, then H
2
O; (ii) PCl
5
, distillation; (iii) (S)-(À)-2-Aminomethyl-1-Boc-pyrrolidine; (iv) trifluoroacetic acid; and (v) [ C]CH
3
I, dimethylformamide/triethylamine,
room temperature, 6 min., grey circles stand for BH, and black circles stand for C.
corresponding acid by treatment with n-BuLi in THF followed by trapped, distilled under continuous helium flow and finally
reaction with dry ice. After hydrolysis, the acid was reacted with introduced in an HPLC loop pre-charged with a solution of the
phosphorous pentachloride in dry toluene and distilled to yield precursor and a base. During optimization runs, the reaction
the acid chloride, which was reacted with (S)-(À)-2-aminomethyl- crude was analyzed by HPLC to determine RCC.
11
1-Boc-pyrrolidine (prepared according to Scheme 2) to yield the
In our first attempts to synthesize [ C]-1, DMSO was used
amide which gave the desired precursor (as trifluoroacetate salt) as a solvent, and triethylamine was used as a base, while the
after treatment with TFA.
The synthesis of [ C]CH
amount of precursor was maintained at 1 mg (2.6 μmol). The
I was carried out using the gas phase reaction time was initially fixed to 6 min. None of the different
1
1
3
method, which was selected because the resulting radiotracers base/precursor molar ratios used yielded the desired
have higher specific activity than those prepared using the radiotracer. When DMF was used as solvent, RCC values in
1
8
‘
wet method’. A methodology is well established in our the range 6.5 ± 2.1–31.4 ± 4.8% were obtained for different
1
1
laboratory. [ C]CH
4
was directly generated in an IBA Cyclone precursor/base molar ratios (entries #1–#5, Table 1).
8/9 cyclotron by irradiation of a gas N /H mixture with Interestingly, an increase in the amount of base above 72 μmol
8 MeV protons. The radioactive gas was allowed to react with did not lead to higher RCCs (30.3 ± 4.4% when 144 μmol of
1
1
2
2
11
iodine at 720°C to form [ C]methyl iodide, which was first base were added). The same experimental conditions were
Scheme 2. (i) Synthesis of (S)-(À)-2-aminomethyl-1-Boc-pyrrolidine. Reagents: (i) Boc
dimethylformamide and then H O.
2 3 2 3 3
O, NaHCO (s), H O/THF; (ii) TsCl, pyridine; (iii) NaN , DMSO, microwave; and (iv) PPh ,
2
11
Table 1. Experimental conditions and radiochemical conversion for the preparation of [ C]-1
Entry
Precursor (μmol)
Base (μmol)
Base/precursor molar ratio
Rt (min)
RCC (%)*
1
2
3
4
5
6
7
8
9
2.6
2.6
2.6
2.6
2.6
5.2
5.2
2.6
2.6
2.6
7.2
14.4
28.8
72
144
28.8
72
28.8
72
72
2.8
5.5
11
28
55
11
28
11
28
28
6
6
6
6
6
6
6
1
1
6.5 ± 2.1
8.2 ± 3.3
9.0 ± 1.8
31.4 ± 4.8
30.3 ± 4.4
33.1 ± 6.2
31.7 ± 2.3
4.3 ± 3.0
10.5 ± 2.4
32.5 ± 6.1
1
0
10
All experiments were performed using dimethylformamide as solvent.
Values are expressed as mean ± standard deviation (n = 3 except entries #8 and #9, n = 2).
*RCC: radiochemical conversion, calculated from chromatographic profiles.
J. Label Compd. Radiopharm 2014, 57 209–214
Copyright © 2013 John Wiley & Sons, Ltd.
www.jlcr.org

V. Gómez-Vallejo et al.
employed using a higher amount of precursor (2mg), but the RCCs purity at the end of the synthesis was > 98% in all cases, and
did not improve significantly (entries #6 and #7, Table 1). Longer the radiotracer showed to be stable in ethanol/physiologic saline
reaction times (up to 10 min) also did not enhance RCCs (entry
10), while shorter reaction times yielded lower RCCs (entries #8
and #9). [ C]methyl triflate was also investigated as methylating
agent under identical experimental conditions, but no desired
radiotracer could be detected in any case, even when other bases
solution at least for 60 min after end of the synthesis
radiochemical purity >95% at t = 60 min). As expected, both
the amount and the concentration of radioactivity (245 MBq
and 81.7 MBq/mL, respectively) were sufficient to perform
in vivo experiments.
#
(
1
1
(
(
NaOH 5 M aqueous solution, 2,4,6-trimethylpyridine) were used
results not shown).
Although the RCCs are not high when compared with
In vivo studies
typical values obtained for single methylation reactions using
1
1
11
[
C]CH3I, the capability to generate high amounts of The WB biodistribution of [ C]-1 in rats was measured as the
1
1
radioactivity in the [ C]CH
4
target (up to 37 GBq in 25 min decay-corrected percentage of injected dose per gram of tissue
irradiation time) should allow the preparation of enough (% ID/g). Figure 3 shows the data corresponding to the
1
1
11
[
C]-1 for further in vivo investigation. On the basis of this distribution of [ C]-1 in heart, bladder, kidneys, liver, brain,
assumption, a new set of experiments were performed under and lungs at different time points after administration of the
the experimental conditions shown in entry #4; a purification radiotracer. The low amount of radioactivity detected in
step using HPLC (water/MeCN 10/90, Experimental Section) the heart suggests a fast clearance of the radiotracer from
was used. Under these conditions, the desired product could the bloodstream. High initial uptake of radioactivity was
be purified in 20–21 min. Attempts to shorten retention times found in the kidneys, liver, and lungs, followed by a decrease
1
1
for [ C]-1 were unsuccessful because of the presence of a of radioactivity in these organs thereafter. A significant
uptake of the radiotracer was detected in the brain;
the amount of radioactivity peaked at t = 2.5 min (%ID/
g = 9.9± 1.2%) slowly decreasing to the end of the study (%ID/
g = 4.7 ± 0.8% at t = 60 min). The accumulation of the tracer in
the bladder confirms the elimination of the tracer by the urinary
system, although significant accumulation was also detected in
small intestine and stomach at t > 8 min (Figure 4).
When brain scans were performed, a good blood brain
barrier penetration of the radiotracer was observed. However,
slightly higher uptake was measured in the cerebellum when
compared with striatum, suggesting a high unspecific uptake
of the radiotracer (Figure 5). Although this difference was not
statistically significant, the high uptake in a region with low
density of D2 receptors suggests that this tracer is not
non labeled and unidentified impurity with slightly shorter
retention time (17–19 min, Figure 2) which co-eluted with
1
1
[
C]-1 when higher MeCN/water ratios were used.
Three complete runs including purification were performed
under optimal experimental conditions starting from 7.4 GBq of
11
[
4
C]CH . After collecting the purified fraction and reformulating
via C-18 trapping, elution with ethanol and reconstitution,
11
2
45 ± 38 MBq of pure [ C]-1 were obtained in average
production times of 50 min (decay corrected radiochemical yield
of 18.2 ± 2.8%). Specific radioactivity values were estimated to be
in the range 80–120 GBq/μmol (EOS) according to historical
values obtained in our laboratory with the same automatic
configuration. The identity of the desired radiotracer was
confirmed by HPLC-MS on the collected fraction after complete
appropriate for the in vivo assessment of D receptor density.
2
+
decay. The molecule was detected as [M + H] (m/z = 286.3, The high uptake might be due to the lipophilic character of
retention time = 4.35 min, Experimental Section). Radiochemical the radiotracer, resulting from the presence of the carborane
11
Figure 2. Chromatographic profiles corresponding to the purification of [ C]-1. Radiometric detector (lower trace) and ultraviolet detector (upper trace) profiles are shown.
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Copyright © 2013 John Wiley & Sons, Ltd.
J. Label Compd. Radiopharm 2014, 57 209–214

V. Gómez-Vallejo et al.
1
1
Figure 3. Biodistribution of [ C]-1 in rat tissues (n = 3) as determined by positron emission tomography. Radioactivity is expressed as the percentage of the injected dose
per gram of tissue (% ID/g; mean ± SD).
1
1
Figure 4. Positron emission tomography (PET) coronal projection images of [ C]-1 signal at different time points after tracer injection. The PET image is co-registered
with the CT image to localize the PET signal anatomically. This figure is available in color online at wileyonlinelibrary.com/journal/jlcr
Conclusions
11
The synthesis of C-labeled (1,7-dicarba-closo-dodecaboran-1-
yl)-N-{[(2S)-1-ethylpyrrolidin-2-yl]methyl}amide was achieved by
11
reaction of the demethylated precursor with [ C]CH
under basic conditions. Moderate radiochemical yields
18.2 ± 2.8%, decay corrected), and excellent radiochemical
purities (>98%) were obtained in average synthesis times of
50 min. The radiotracer showed a fast uptake in liver, kidneys,
3
I in DMF
(
~
11
and lungs at short times after [ C]-1 administration followed
by a significant increase in the bladder. Brain scans showed
non-specific binding. These results suggest that [ C]-1 is not
11
suitable to be used as D receptor ligand.
2
Figure 5. Time activity curves for cerebellum and striatum after administration of
Acknowledgements
1
1
[
C]-1. Radioactivity is expressed as the percentage of the injected dose per gram
of tissue (% ID/g; mean ± SD).
The authors would like to thank the Departamento de Industria,
Comercio y Turismo of the Basque Government and the Ministerio
de Economía y Competitividad (former Ministerio de Ciencia e
unit. Future work will be focussed on appropriate substitution
of the carborane cage and generation of the nido species to Innovación, Grants CTQ2009-08810 and CENIT CIN/1559/2009)
decrease hydrophobicity.
for financial support.
J. Label Compd. Radiopharm 2014, 57 209–214
Copyright © 2013 John Wiley & Sons, Ltd.
www.jlcr.org

V. Gómez-Vallejo et al.
[
9] S. C. Fowler, T. J. Zarcone, E. Vorontsova, R. Chen, Int. J. Dev. Neurosci.
Conflict of Interest
2
002, 20(3–5), 309.
The authors did not report any conflict of interest.
[10] A. Martín, V. Gómez-Vallejo, E. San Sebastián, D. Padró, I. Markuerkiaga,
I. Llarena, J. Llop, J. Cerebr. Blood F Met. 2012, 33, 244.
11] A. M. Catafau, M. Suarez, S. Bullich, J. Llop, G. Nucci, R. N. Gunn, C.
[
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