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3H); 13C NMR (75 MHz, DMSO): d=165.15 (s), 160.21 (s), 154.97 (s),
151.69 (d, J=243.0 Hz), 146.79 (s), 146.40 (d, J=10.3 Hz), 133.06 (s),
132.98 (s), 127.45 (s), 124.00 (s), 115.44 (d, J=18.0 Hz), 114.15 (s),
102.90 (s), 56.45 (s), 42.10 (s), 20.19 (s), 15.01 ppm (s).
J=3.1, 1.5 Hz), 102.76 (s), 36.17 (s), 20.18 (s), 15.01 ppm (s); MS: m/
z [M+1]+ =365.
General procedure for 11C-methylation: The general procedure
for 11C-labeling was described previously[46] with minor modifica-
tion in this work. Briefly, [11C]methyl iodide ([11C]CH3I) was synthe-
sized from cyclotron-produced [11C]CO2, which was produced by
14N(p,a)11C nuclear reaction. Briefly, [11C]CO2 was bubbled into a so-
lution of LiAlH4 (0.4m in THF, 300 mL). After evaporation, the re-
maining reaction mixture was treated with hydroiodic acid (57%
aqueous solution, 300 mL). The resulting [11C]CH3I was transferred
under helium gas with heating into a pre-cooled (À15 to À208C)
reaction vessel containing precursor (1.0 mg), NaOH (6.0 mL, 0.5m)
and anhydrous DMF (300 mL). After the radioactivity reached a pla-
teau during transfer, the reaction vessel was warmed to 808C and
maintained for 5 min. CH3CN/H2O+0.1% Et3N (0.5 mL) was added
to the reaction mixture, which was then injected to a semi-prepa-
rative HPLC system. HPLC purification was completed on a Capcell
Pak UG80 C18 column (10 mm IDꢂ250 mm) using a mobile phase
of CH3CN/H2O+0.1% Et3N. The radioactive fraction corresponding
to the desired product was collected in a sterile flask, evaporated
to dryness in vacuo, and reformulated in a saline solution (3 mL)
containing 100 mL of 25% ascorbic acid in sterile water and 100 mL
of 20% Tweenꢁ 80 in ethanol. Radiochemical and chemical purity
were measured by analytical HPLC (Capcell Pak UG80 C18, 4.6 mm
ID ꢂ 250 mm, UV at 254 nm; CH3CN/H2O+0.1% Et3N at a flow rate
of 1.0 mLminÀ1). The identity of [11C]11 a–c was confirmed by the
co-injection with unlabeled 11 a–c.
5-amino-N-(2,5-difluoro-4-methoxybenzyl)-3,4-dimethylthie-
no[2,3-c]pyridazine-6-carboxamide (11 b): According to the gener-
al procedure for the condensation reaction, compound 11 b was
prepared in 81% yield as a yellow solid. Melting point: 235–2378C;
1H NMR (300 MHz, DMSO): d=8.57 (t, J=5.6 Hz, 1H), 7.14 (ddd, J=
23.0, 11.6, 7.1 Hz, 2H), 6.94 (s, 2H), 4.38 (d, J=5.6 Hz, 2H), 3.82 (s,
3H), 2.70 (s, 3H), 2.68 ppm (s, 3H); 13C NMR (75 MHz, DMSO): d=
165.27 (s), 160.23 (s), 156.21 (dd, J=241.0, 2.2 Hz), 154.99 (s),
148.03 (dd, J=239.7, 2.8 Hz), 147.33 (dd, J=12.3, 10.7 Hz), 146.92
(s), 133.07 (s), 127.35 (s), 117.94 (dd, J=17.7, 5.9 Hz), 116.32 (dd, J=
20.7, 6.3 Hz), 102.62 (s), 102.27 (d, J=1.6 Hz), 56.93 (s), 36.08 (s),
20.19 (s), 15.01 ppm (s).
5-amino-N-(2,3-difluoro-4-methoxybenzyl)-3,4-dimethylthie-
no[2,3-c]pyridazine-6-carboxamide (11 c): According to the gener-
al procedure for the condensation reaction, compound 11 c was
prepared in 66% yield as a yellow solid. Melting point: 217–2198C;
1H NMR (300 MHz, DMSO): d=8.62 (t, J=5.6 Hz, 1H), 7.16–6.95 (m,
4H), 4.42 (d, J=5.6 Hz, 2H), 3.84 (s, 3H), 2.71 (s, 3H), 2.69 ppm (s,
3H); 13C NMR (75 MHz, DMSO): d=165.20 (s), 160.23 (s), 154.94 (s),
148.85 (dd, J=245.0, 10.4 Hz), 147.91 (dd, J=7.7, 3.0 Hz), 146.89
(s), 140.32 (dd, J=245.0, 14.3 Hz), 133.29 (s), 127.49 (s), 123.89 (dd,
J=5.1, 4.4 Hz), 120.08 (dd, J=12.3, 1.3 Hz), 109.27 (d, J=3.2 Hz),
102.76 (s), 56.96 (s), 36.24 (s), 20.12 (s), 15.03 ppm (s).
5-amino-N-(3-fluoro-4-[11C]methoxybenzyl)-3,4-dimethylthie-
no[2,3-c]pyridazine-6-carboxamide
([11C]VU0467485/
5-amino-N-(3-fluoro-4-hydroxybenzyl)-3,4-dimethylthieno[2,3-
c]pyridazine-6-carboxamide (12a): According to the general pro-
cedure for the condensation reaction, compound 12a was pre-
pared in 41% yield as a yellow solid. Melting point: 188–1908C;
1H NMR (300 MHz, DMSO): d=9.70 (s, 1H), 8.56 (t, J=5.9 Hz, 1H),
7.07 (dd, J=12.3, 1.3 Hz, 1H), 6.98–6.84 (m, 4H), 4.31 (d, J=5.9 Hz,
2H), 2.70 (s, 3H), 2.68 ppm (s, 3H); 13C NMR (75 MHz, DMSO): d=
165.10 (s), 160.20 (s), 154.95 (s), 151.18 (d, J=240.5 Hz), 146.74 (s),
144.05 (d, J=12.2 Hz), 132.99 (s), 131.42 (d, J=5.8 Hz), 127.41 (s),
124.00 (d, J=2.9 Hz), 117.95 (d, J=3.0 Hz), 115.63 (d, J=18.5 Hz),
[11C]AZ13713945/[11C]11a): According to the general procedure[46]
for the 11C-methylation, the retention time for [11C]11 a was
12.0 min. The synthesis time was ~40 min from end-of-bombard-
ment. HPLC purification was completed on a Capcell Pak UG80 C18
column (10 mm IDꢂ250 mm) using a mobile phase of CH3CN/H2O
(v/v, 4:6)+0.1% Et3N at a flow rate of 4.0 mLminÀ1. Radiochemical
and chemical purity were measured by analytical HPLC (Capcell
Pak UG80 C18, 4.6 mm IDꢂ250 mm, UV at 254 nm; CH3CN/H2O (v/v,
4:6)+0.1% Et3N at a flow rate of 1.0 mLminÀ1). Radiochemical
yield was 31.3% decay-corrected based on [11C]CO2 with >99% ra-
diochemical purity and greater than 2 CimmolÀ1 molar activity.
102.98 (s), 42.09 (s), 20.19 (s), 15.00 ppm (s); MS: m/z [M+1]+
=
347.
5-amino-N-(2,5-difluoro-4-[11C]methoxybenzyl)-3,4-dimethylthie-
no[2,3-c]pyridazine-6-carboxamide ([11C]11b): According to the
general procedure[46] for the 11C-methylation, the retention time for
[11C]11 b was 8.1 min. The synthesis time was ~35 min from end-
of-bombardment. HPLC purification was completed on a Capcell
Pak UG80 C18 column (10 mm ID ꢂ 250 mm) using a mobile phase
5-amino-N-(2,5-difluoro-4-hydroxybenzyl)-3,4-dimethylthie-
no[2,3-c]pyridazine-6-carboxamide (12b): According to the gen-
eral procedure for the condensation reaction, compound 12b was
1
prepared in 56% yield as a yellow solid. H NMR (300 MHz, DMSO):
d=10.25 (s, 1H), 8.53 (t, J=5.6 Hz, 1H), 7.15–6.70 (m, 4H), 4.35 (d,
J=5.6 Hz, 2H), 2.69 (s, 3H), 2.68 ppm (s, 3H); 13C NMR (75 MHz,
DMSO): d=165.23 (s), 160.22 (s), 155.98 (dd, J=240.5, 1.9 Hz),
154.94 (s), 147.77 (dd, J=236.6, 2.5 Hz), 146.86 (s), 145.16 (dd, J=
14.3, 11.8 Hz), 133.05 (s), 127.35 (s), 116.79 (dd, J=6.0, 4.0 Hz),
116.53 (dd, J=7.3, 6.1 Hz), 105.06 (dd, J=26.4, 3.1 Hz), 102.71 (s),
36.09 (s), 20.16 (s), 15.00 ppm (s); MS: m/z [M+1]+ =365.
of CH3CN/H2O (v/v, 45:55)+0.1% Et3N at
a flow rate of
5.0 mLminÀ1. Radiochemical and chemical purity were measured
by analytical HPLC (Capcell Pak UG80 C18, 4.6 mm IDꢂ250 mm, UV
at 254 nm; CH3CN/H2O (v/v, 45:55)+0.1% Et3N at a flow rate of
1.0 mLminÀ1). Radiochemical yield was 38.8% decay-corrected
based on [11C]CO2 with >99% radiochemical purity and greater
than 2 CimmolÀ1 molar activity.
5-amino-N-(2,3-difluoro-4-hydroxybenzyl)-3,4-dimethylthie-
no[2,3-c]pyridazine-6-carboxamide (12c): According to the gener-
al procedure for the condensation reaction, compound 12c was
prepared in 81% yield as an orange red solid. Melting point: 245–
2478C; 1H NMR (300 MHz, DMSO): d=10.26 (s, 1H), 8.56 (t, J=
5.5 Hz, 1H), 7.02–6.70 (m, 4H), 4.39 (d, J=5.5 Hz, 2H), 2.70 (s, 3H),
2.69 ppm (s, 3H); 13C NMR (75 MHz, DMSO): d=165.18 (s), 160.23
(s), 154.97 (s), 149.24 (dd, J=244.5, 10.6 Hz), 146.85 (s), 145.91 (dd,
J=9.0, 2.8 Hz), 139.97 (dd, J=242.1, 14.2 Hz), 133.08 (s), 127.37 (s),
123.81 (dd, J=5.3, 4.2 Hz), 118.12 (dd, J=12.2, 1.4 Hz), 113.00 (dd,
5-amino-N-(2,3-difluoro-4-[11C]methoxybenzyl)-3,4-dimethylthie-
no[2,3-c]pyridazine-6-carboxamide ([11C]11c): According to the
general procedure[46] for the 11C-methylation, the retention time for
[11C]11 c was 8.5 min. The synthesis time was ~35 min from end-of-
bombardment. HPLC purification was completed on a Capcell Pak
UG80 C18 column (10 mm IDꢂ250 mm) using a mobile phase of
CH3CN/H2O (v/v, 45:55)+0.1% Et3N at a flow rate of 5.0 mLminÀ1
.
Radiochemical and chemical purity were measured by analytical
ChemMedChem 2018, 13, 1 – 8
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