H. Watanabe, et al.
Bioorganic&MedicinalChemistryLetters30(2020)127562
Scheme 2. Radiosynthesis of 3-phenylcoumarin derivatives. Reagents: (a) [125I]NaI, H2O2, 1 N HCl.
18, 21, 24, and 27) according to Scheme 1. The 3-phenylcoumarin
aryl acetic acid, and Et3N by following the method reported pre-
viously.20 The free amino derivatives (4, 5, and 6) were prepared from
nitro derivatives (1, 2, and 3) by reduction with SnCl2 in yields of 54,
74, and 89%, respectively. The amino derivatives (4, 5, and 6) were
converted to monomethylamino derivatives (10, 11, and 12) or di-
previously.21,22 The bromo derivatives (4, 5, 10, 11, 16, 17, 22, and
23) were converted to the tributyltin derivatives (7, 8, 13, 14, 19, 20,
25, and 26) by the exchange reaction of bromine to tributyltin in yields
of 11–53%. These tributyltin compounds were reacted with iodine at
room temperature to give the iodo derivatives (9, 15, 21, and 27) in
yields of 70–99%.
Table 1
Brain uptake of radioactivity after intravenous injection of [125I]6, [125I]9,
[
125I]12, [125I]15, [125I]18, [125I]21, [125I]24, and [125I]27 in normal micea
and the ratio of their radioactivity accumulation (2 min/60 min).
Compd
%ID/g in the brain
Ratio
2 min
10 min
30 min
60 min
2 min/
60 min
[
[
[
[
[
[
[
[
125I]6
3.67
4.79
0.88 2.77
0.75 5.60
0.33 3.64
0.24 2.06
0.20 2.91
0.29 3.12
0.24 2.56
0.61 1.90
0.25 1.27
0.17 0.65
0.06
0.16
0.11
0.04
0.10
0.18
5.6
4.3
6.2
4.5
6.1
2.8
125I]9
0.44 2.63
1.23 1.34
0.16 1.07
0.17 1.44
0.27 1.74
0.21 0.74
0.32 0.44
0.43 1.11
0.21 0.61
0.12 0.55
0.23 0.56
0.16 1.00
0.07 0.27
0.05 0.13
125I]12 3.76
125I]15 2.48
125I]18 3.40
125I]21 2.84
125I]24 5.02
125I]27 2.87
0.03 18.6
0.01 22.1
We used the tributyltin derivatives as the precursor materials for
radioiodination. 125I-labeled 3-phenylcoumarin derivatives ([125I]6,
a
Each value represents the mean
SD of five animals.
[
125I]9, [125I]12, [125I]15, [125I]18, [125I]21, [125I]24, and [125I]27)
were prepared by an iododestannylation reaction using [125I]NaI and
hydrogen peroxide as the oxidant (Scheme 2). The radioiodinated
chromatography (RP-HPLC) after the radioiodination reaction. We
identified the radioiodinated ligands from their HPLC profiles by co-
injection with non-radioiodinated compounds. [125I]6, [125I]9, [125I]
12, [125I]15, [125I]18, [125I]21, [125I]24, and [125I]27 were obtained in
a radiochemical yield of 63.7, 78.8, 69.9, 75.5, 80.3, 88.1, 86.5, and
71.8%, respectively, with a radiochemical purity of over 95%.
normal mouse brain. Since all compounds except [125I]9 and [125I]15
showed low radioactivity in the thyroid until 60 min postinjection
(0.02–0.54% ID) (Table S1), they are stable against deiodination in vivo.
In order to evaluate selective binding affinity to myelin in vivo, we
performed ex vivo autoradiography (ARG) using brain sections prepared
from normal mice at 60 min after injection of 125I-labeled 3-phe-
nylcoumarin derivatives (Fig. 2). The location of myelin was confirmed
[
First, we performed biodistribution experiments to evaluate uptake
into and retention in the brain after the injection of 125I-labeled 3-
phenylcoumarin derivatives into wild-type mice (Table 1). All com-
injected dose (ID)/g, at 2 min postinjection. This suggested that all 125I-
labeled 3-phenylcoumarin derivatives have the potential of binding to
myelin in the brain. Among these compounds, [125I]24 and [125I]27,
which have a 1,3-dioxolan group, showed a high 2 min/60 min ratio.
On the other hand, [125I]21 exhibited the lowest 2 min/60 min ratio
among these derivatives, indicating that [125I]21 was retained in the
accumulation in the white matter, which contains myelin. On the other
hand, [125I]24 and [125I]27 did not show marked radioactivity accu-
mulation in the brain due to low accumulation in the brain at 60 min
postinjection. To compare the selective binding affinity for myelin
among 3-phenylcoumarin derivatives, the region of interest (ROI) was
set to white and gray matter of brain sections (Fig. S2), and the ratio of
radioactivity accumulation in the white matter against the gray matter
was calculated (Table 2). Due to the extremely low radioactivity on the
brain sections, it was difficult to calculate the ratios of [125I]24 and
3