tion. Yields are for isolated and spectroscopically pure material,
unless otherwise stated. Reaction progress was monitored by
using thin-layer chromatography (0.25 mm E. Merck silica plates,
60F-254), visualized by fluorescence quenching with UV light at
254 nm or by iodine staining. Silica gel chromatography was car-
ried out by using E. Merck silica gel (60 pore size, particle size
40–63 nm). 1H NMR spectra were recorded at 400 MHz and
13C NMR spectra at 100 MHz by using a Bruker Avance III NMR
spectrometer. The chemical shifts for 1H NMR and 13C NMR were
referenced to TMS through residual solvent signals (1H, CDCl3 at
intestine with contents that, in conjunction with rapid clear-
ance from blood, indicate fast elimination kinetics. Very low
levels of activity were detected in all other organs. Although
the AT2R has been previously detected in the pancreas and
sexual organs,[42] only low activity was detected in these
organs.
2.6. MicroPET-CT
1
7.26 ppm; 13C, CDCl3 at 77.16 ppm; H, [D6]DMSO at 2.45 ppm; 13C,
The fused PET/CT images over the abdomen showed the same
distribution pattern for the anaesthetized male rats (Figure 3)
as that determined by ex vivo biodistribution studies when
using un-sedated female rats. The only organ that was clearly
distinguishable was the liver. However, by using early frames,
regions of interest (ROIs) could be drawn also for the aorta
and the left kidney, and time activity curves were generated.
The kinetics of [11C]C21 in these organs are shown in Figure S4
in the Supporting Information.
[D6]DMSO at 39.43 ppm). LC–MS was performed on an instrument
equipped with a CP-Sil 8 CB capillary column (503.0 mm, particle
size 2.6 mm, pore size 100 ), operating at an ionization potential
of 70 eV, using a 2 min 5–100% CH3CN/H2O gradient (0.05%
HCOOH in both CH3CN & H2O). Accurate mass values were deter-
mined by using an electrospray ionization source with a 7-T hybrid
ion trap and a TOF detector or through chemical ionization by
using ammonia as carrier gas. Sulfonyl azides 1a–1g,[29] precursors
1h–1l,[11] and the non-labeled standards for compounds 2a–2h
and 3a–3d[28] were synthesized following the literature procedures
and spectral data were in agreement with published values.
3-[4-[(1H-Imidazol-1-yl)methyl]phenyl]-5-isobutylthiophene-
2-sulfonamide (1m)
1l (0.29 g, 0.68 mmol) was dissolved in 2 mL TFA and stirred over-
night at ambient temperature. Upon full consumption of starting
material (as confirmed by LC–MS), the volatiles were evaporated.
The crude product (colorless oil) was used in the next step without
further purification (0.25 g, 89%). Rf (SiO2)=0.24 (1:9 MeOH/DCM);
1H NMR (400 MHz, [D6]DMSO): d=9.14 (d, J=1.3 Hz, 1H), 7.82–7.74
(m, 1H), 7.65–7.62 (m, 4H), 7.62–7.60 (m, 1H), 7.48–7.38 (m, 2H),
6.91 (t, J=0.8 Hz, 1H), 5.45 (s, 2H), 2.68 (dd, J=7.0, 0.8 Hz, 2H),
1.99–1.80 (m, 1H), 0.94 ppm (d, J=6.6 Hz, 6H); 13C NMR (100 MHz,
[D6]DMSO): d=146.6, 141.8, 137.9, 136.2, 135.4, 135.1, 130.13,
130.08, 128.2, 122.3, 121.9, 51.5, 38.5, 30.4, 22.4 ppm; MS (ESI): m/z
calcd for C18H23N3O2S2: 376.1153 [M+H+]; found: 376.1163.
Figure 3. PET/CT image, showing in vivo distribution of [11C]C21 in a healthy
male rat. Grey scale (CT), 200–1500 Hounsfield units, colour scale (PET)
SUV=0 to 20 (black to red). White arrows show liver in 3 projections and
kidneys in transaxial projection.
3. Conclusions
A general methodology for the 11C-labeling of sulfonyl carba-
mates in a RhI-mediated multicomponent reaction has been
developed and demonstrated by the preparation of 12 11C-sul-
fonyl carbamates. The radiolabeling of a potent, non-peptide
AT2R agonist (C21) was then successfully performed and the
isolated compound was found to bind specifically in prostate
tumor cells expressing AT2R. The biological evaluation of
[11C]C21 indicates rapid metabolism and excretion, thus pre-
cluding its use as a PET tracer. However, given the potential
utility of an AT2R-selective imaging agent in individualized
management of prostate cancer therapy, these results provide
an entry point into the development of future tracers to meet
this need.
3-[4-[(1H-Imidazol-1-yl)methyl]phenyl]-5-isobutylthiophene-
2-sulfonyl azide (1n)
To a stirred mixture of 1m (55.1 mg, 0.14 mmol) and K2CO3
(86.1 mg, 0.62 mmol) in 1:1 iPrOH/H2O (10 mL) was added imida-
zole-1-sulfonyl azide hydrogen sulfate (56.8 mg, 0.21 mmol). The
reaction mixture was stirred for 16 h and then quenched by the
addition of 10 mL NaHCO3. EtOAc (20 mL) was added and the re-
sulting aqueous phase was extracted with 20 mL EtOAc. The com-
bined organics were washed with brine, dried over Na2SO4, and
concentrated in vacuo. The crude yellow liquid obtained directly
after workup was of sufficient purity (ca. 2% starting material, as
confirmed by 1H NMR) to be used directly in RhI-mediated carbony-
lation chemistry. Purification by using silica gel chromatography
(0–10% MeOH in CHCl3) significantly reduced the isolated yield
(colorless liquid, 11 mg, 20%), possibly owing to stability issues
with the sulfonyl azide moiety. The purified compound was stable
Experimental Section
Chemistry
1
for >1 month at À218C. Rf (SiO2)=0.32 (1:9 MeOH/DCM; H NMR
General
(400 MHz, CDCl3): d=7.49 (s, 1H), 7.33–7.22 (m, 2H), 7.03–6.98 (m,
2H), 6.91 (t, J=0.8 Hz, 1H), 6.72 (s, 1H), 6.63 (s, 1H), 4.98 (s, 2H),
2.51 (dd, J=7.1, 0.8 Hz, 2H), 1.82–1.58 (m, 1H), 0.78 ppm (d, J=
6.6 Hz, 6H); 13C NMR (100 MHz, CDCl3): d=153.8, 147.2, 136.1,
135.2, 134.1, 131.0, 130.9, 130.6, 128.5, 122.5, 121.1, 39.8, 31.1,
All reagents were purchased at the highest commercial quality and
used without further purification. Solvents used for extraction and
silica gel chromatography (EtOAc, hexanes, n-pentane, dichlorome-
thane and methanol) were used without purification or desicca-
ChemistryOpen 2016, 5, 566 –573
570
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