Positron emission tomography to elucidate pharmacokinetic differences of regioisomeric retinoid x receptor agonists

Article abstract of DOI:10.1021/ml500511m

RXR partial agonist NEt-4IB (2a, 6-[ethyl-(4-isobutoxy-3-isopropylphenyl)amino]pyridine-3-carboxylic acid: EC₅₀ = 169 nM, E_max = 55%) showed a blood concentration higher than its E_max after single oral administration at 30 mg/kg to mice, and repeated oral administration at 10 mg/kg/day to KK-A^y mice afforded antitype 2 diabetes activity without the side effects caused by RXR full agonists. However, RXR full agonist NEt-3IB (1a), in which the isobutoxy and isopropyl groups of 2a are interchanged, gave a much lower blood concentration than 2a. Here we used positron emission tomography (PET) with tracers [¹¹C]1a, [¹¹C]2a and fluorinated derivatives [¹⁸F]1b, [¹⁸F]2b, which have longer half-lives, to examine the reason why 1a and 2a exhibited significantly different blood concentrations. As a result, the reason for the high blood concentration of 2a after oral administration was found to be linked to higher intestinal absorbability together with lower biliary excretion, compared with 1a.

Full text of DOI:10.1021/ml500511m

Letter
pubs.acs.org/acsmedchemlett
Positron Emission Tomography to Elucidate Pharmacokinetic
Differences of Regioisomeric Retinoid X Receptor Agonists
Toshiki Kobayashi,† Yuki Furusawa,† Shoya Yamada,†,‡ Masaru Akehi,§ Fumiaki Takenaka,§
Takanori Sasaki,§ Akiya Akahoshi,§ Takahisa Hanada,§ Eiji Matsuura,§ Hiroyuki Hirano,∥ Akihiro Tai,⊥
and Hiroki Kakuta*,†
†Division of Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences,
1-1-1, Tsushima-Naka, Kita-ku, Okayama 700-8530, Japan
‡Research Fellowship Division, Japan Society for the Promotion of Science, Sumitomo-Ichibancho FS Bldg., 8 Ichibancho,
Chiyoda-ku, Tokyo 102-8472, Japan
§Collaborative Research Center for OMIC, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical
Sciences, 2-5-1 Shikata-Cho, Kita-ku, Okayama 700-8558, Japan
∥SHI Accelerator Service Ltd. 1-17-6 Osaki, Shinagawa-ku, Tokyo 141-0032, Japan
⊥Faculty of Life and Environmental Sciences, Prefectural University of Hiroshima, 562 Nanatsuka-Cho, Shobara, Hiroshima
727-0023, Japan
S
* Supporting Information
ABSTRACT: RXR partial agonist NEt-4IB (2a, 6-[ethyl-(4-isobutoxy-3-isopropylphenyl)amino]pyridine-3-carboxylic acid:
EC50 = 169 nM, Emax = 55%) showed a blood concentration higher than its Emax after single oral administration at 30 mg/kg to
mice, and repeated oral administration at 10 mg/kg/day to KK-Ay mice afforded antitype 2 diabetes activity without the side
effects caused by RXR full agonists. However, RXR full agonist NEt-3IB (1a), in which the isobutoxy and isopropyl groups of 2a
are interchanged, gave a much lower blood concentration than 2a. Here we used positron emission tomography (PET) with
tracers [11C]1a, [11C]2a and fluorinated derivatives [18F]1b, [18F]2b, which have longer half-lives, to examine the reason why 1a
and 2a exhibited significantly different blood concentrations. As a result, the reason for the high blood concentration of 2a after
oral administration was found to be linked to higher intestinal absorbability together with lower biliary excretion, compared with
1a.
KEYWORDS: Nuclear receptors, RXR, PET imaging, pharmacokinetics
pyridine-3-carboxylic acid)10,11 and RXR partial agonist NEt-
exarotene (EC50 = 20 nM, Emax = 100%) (Figure 1), a
Bretinoid X receptor (RXR) agonist, is clinically used for
4IB (2a: 6-[ethyl-(4-isobutoxy-3-isopropylphenyl)amino]-
pyridine-3-carboxylic acid)12 (Figure 1). Compound 1a was
the treatment of cutaneous T cell lymphoma (CTCL) in the
United States1 and is also reported to show curative effects on
designed by introducing a polar alkoxy group into the
hydrophobic moiety to lower the lipophilicity because previous
type-2 diabetes,2 Alzheimer’s disease,3 and Parkinson’s disease4
RXR agonists including bexarotene are quite lipophilic.
However, 2a was obtained as a RXR partial agonist based on
the hypothesis that RXR partial agonists, which only partially
in animal models. However, experience with RXR full agonists,
including bexarotene, has shown that they can cause serious
adverse effects, including hypothyroidism, hepatomegaly,
weight gain, and elevation of blood triglyceride.5−9 Aiming to
create new RXR agonists without these side effects, we have
designed, synthesized, and characterized RXR full agonist NEt-
3IB (1a: 6-[ethyl-(3-isobutoxy-4-isopropylphenyl)amino]-
Received: December 8, 2014
Accepted: January 20, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/ml500511m
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Letter
precursors of 1a and 2a (SI Scheme 2). Removal of the
isopropyl group of 12 and 13 by using AlCl3 afforded 14 and
15, respectively. These compounds were reacted with 11 to
afford 16 and 17, respectively. Catalytic reduction using Pd/C
failed to remove the benzyl protection, but the use of AlCl3
afforded 18 and 19, and the hydroxyl group was converted to a
triflate group to afford 20 and 21, respectively. The
nonradioactive [19F] compounds were synthesized according
to the synthetic scheme for fluorodeoxyglucose (FDG);17
fluorination was performed by the reaction of 20 or 21 with KF
in a mixture of Kryptofix 222 and K2CO3 in MeCN at 90 °C.
Then, after hydrolysis of the ester group with NaOHaq,
neutralization with hydrochloric acid on an ice bath gave 1b
and 2b, respectively. The [18F] derivatives were obtained
similarly, except for the use of [18F]KF and neutralization after
hydrolysis of the ester. Neutralization after hydrolysis was
performed by using p-TSA in MeOH instead of hydrochloric
acid, to ensure compatibility with the eluent used for
preparative chromatography (AcONH4aq/MeOH = 20:80).
After preparative chromatography, [18F]1b and [18F]2b showed
the same retention times as the corresponding 1b and 2b. The
radioactive purity was 98.5% and 99.6% (SI Charts S5 and S6),
and the yield of radioactivity from 18F was 18% (6.2 GBq) and
10% (3.4 GBq), respectively.
Figure 1. Chemical structures of RXR full agonists bexarotene and 1,
and RXR partial agonist 2.
activate RXR, might have minimal side effects since the
reported adverse effects are associated primarily with RXR full
agonists that maximally activate RXRs. Oral administration of
RXR partial agonist 2a gave a considerably higher blood
concentration (AUC = 18.8 h·mg/L at 30 mg/kg, p.o.) than
that of 1a (AUC = 1.14 h·mg/L at 30 mg/kg, p.o.), and indeed,
2a showed a potent glucose-lowering effect in type 2 diabetes
model mice without inducing serious adverse effects.12 Since 1a
is a regioisomer of 2a and its hydrophobic moiety was
constructed simply by interchanging the isobutoxy and
isopropyl groups of 1a, we were interested in the reason for
the significant pharmacokinetic difference between 1a and 2a.
The blood concentration of a drug is determined by the
balance of intestinal absorption, distribution, metabolism, and
excretion. To examine the pharmacokinetics of 1a and 2a in
vivo, we aimed to employ positron emission tomography
(PET). PET imaging can be performed noninvasively and
sequentially, that is, the target compound does not need to be
extracted, and its distribution can be detected with high
resolution.13,14 Moreover, since PET-based pharmacokinetic
studies of bexarotene have been reported,15 it would be of
interest to compare the results for 1a or 2a with the reported
data for bexarotene. PET imaging requires appropriate labeling
of the target compounds, for example, with 11C or 18F.
Therefore, we synthesized [11C]1a and [11C]2a, which possess
an 11C carboxylic acid moiety, and the 18F derivatives 6-{ethyl-
[3-(3-fluoro-2-methylpropoxy)-4-isopropylphenyl]amino}-
nicotinic acid ([18F]1b) and 6-{ethyl-[3-(3-fluoro-2-methyl-
propoxy)-4-isopropylphenyl]amino}nicotinic acid ([18F]2b)
(Figure 1) as PET tracers for the present imaging analyses.
[11C]1a and [11C]2a were synthesized according to
Supporting Information (SI) Scheme 1. The coupling reactions
of 3 and 4 with 5 gave 6 and 7, and N-ethylation at the linking
amino atom afforded 8 and 9, respectively. Lithiation of 8 and 9
was performed by the addition of an ether solution of each
compound at −78 °C via a syringe into the reaction vessel of an
automated reaction chamber, which contained n-BuLi in dry
ether at −20 °C (the lowest temperature setting of the
apparatus).16 After the lithiation, 11CO2 was bubbled into the
reaction vessel, and then excess base was neutralized with p-
toluenesulfonic acid (p-TSA) to give [11C]1a and [11C]2a,
respectively. HPLC analysis revealed that these products
showed the same retention times as the corresponding
unlabeled compounds. The radioactive purity was 99.2% and
98.6% (SI Charts S3 and S4), and the yield of radioactivity from
11CO2 was 2.0% (1.75 GBq) and 0.45% (167 MBq),
respectively.
Since it is reported that introduction of a fluorine atom
decreases the hydrophobicity of the original compound,18 the
polarity and RXRα-agonistic activity of 1b and 2b were
examined. Both HPLC retention times were shortened by
about 5 min, but the order of polarity was maintained (Table
1). Evaluation of RXRα-agonistic activities using luciferase
Table 1. HPLC Retention Time and Luciferase Reporter
a
Gene Assay Data of Each Compound
RXRα
retention time (min)
Emax (%)
EC50 (nM)
1a
1b
2a
2b
12.7
7.63
11.7
6.70
114
98
0
19
6
3
5
2
5
12
55
169
3
52
450 30
a
Conditions: HPLC analyses were performed by using an Inertsil
ODS-3 column (4.6 i.d. × 100 mm, 3 μm, GL Sciences, Tokyo, Japan).
The flow rate was 0.7 mL/min with methanol/25 mM ammonium
acetate (adjusted with acetic acid to pH 5.0) (80:20 v/v) as the mobile
phase. The UV absorbance was monitored at 260 nm. Luciferase
activity of bexarotene at 1 μM was defined as 100%. EC50 values were
determined from full dose−response curves in COS-1 cells. Data
shown are the average (n = 4−5) SEM.
transcription assay in COS-1 cells revealed that compounds 1b
and 2b showed full RXRα-agonistic activity and partial RXRα-
agonistic activity, respectively, like 1a and 2a (Table 1). While
the addition of a fluorine atom in going from 1a to 1b did not
greatly affect the EC50, the addition of a fluorine atom in going
from 2a to 2b had a more profound effect on the EC50. A
possible explanation of this difference is that small perturba-
tions in potent agonists do not exhibit as large binding/
activation effects as small perturbations in partial agonists.
Each PET tracer was dissolved in EtOH and then diluted
with saline to 10 MBq, and the diluted solution was
administered to mice. Then, PET scanning was performed for
30 min. The data were reconstructed at selected times, and the
radioactivity of the whole body and each organ of the mice was
Compounds 1b and 2b were synthesized from 12 and 13,
respectively,10−12 which have already been reported as
B
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Letter
calculated in Bq. The pharmacokinetics using each tracer was
compared in terms of the percentage of injected dose (%ID)
values, i.e., the radioactivity of each organ (Bq) per the
radioactivity of the whole body (Bq).
To compare the time dependency of the blood concentration
of each compound, radioactivity in blood was calculated as %
ID/mL by dividing the %ID value in the heart by the heart
volume (Figures 2a,b and SI Figure S1a). The AUC values from
via the biliary route. In addition, both compounds exhibited
enterohepatic circulation, being reabsorbed from the small
intestine, taken up by enterocytes and transported back to the
liver (SI Movies S1 and S2).
To compare the pharmacokinetics in detail, the radioactivity
in each organ was quantified. Regions of interest (ROIs) were
defined using PET/CT imaging data and the radioactivity (%
ID) at each organ at each time was calculated (Figure 3 and SI
Figure 2. Real-time changes in region of interest (ROI) of the PET
images with [18F]1b (closed or open green circle) and [18F]2b (closed
or open blue squares). Time course of (a) [18F]1b administered p.o. or
i.v. and (b) [18F]2b administered p.o. or i.v. were obtained from the
mean pixel radioactivity in the ROI of the PET images acquired after
administration. Data shown are the average (n = 3−5) SEM.
time 0 to 30 min for [18F]1b and [18F]2b after intravenous
injection were 17 h·%ID/mL and 27 h·%ID/mL, respectively.
The [11C] derivatives gave similar results (SI Figure S1a). Since
18F has a longer half-time than 11C, subsequent PET analyses
were performed with [18F]1b or [18F]2b. AUC values after oral
administration were 3.1 h·%ID/mL for [18F]1b and 12 h·%ID/
mL for [18F]2b. The AUC ratio of [18F]2b to [18F]1b was
about 1.6-fold for intravenous injection and about 4-fold for
oral administration. Thus, the difference of blood concentration
after oral administration of each compound is thought to be
due to, at least in part, different gastrointestinal absorption
characteristics. The bioavailability was calculated as the ratio of
dose-corrected AUC after oral administration to that after
intravenous injection, and 0.18 for [18F]1b and 0.43 for [18F]
2b, indicating that [18F]2b is preferable for oral administration.
In the case of intravenous injection, the difference of blood
concentration between the two compounds would be due to a
difference of distribution or excretion. Therefore, it is suggested
that the difference of blood concentration between the two
regioisomers in the case of oral administration may be a
consequence of differences in intestinal absorption, distribution,
and excretion.
Figure 3. Decay-corrected whole-body coronal PET/CT images of
mice from static scans at 0−1, 4−5, 11−14, and 25−30 min after
administration of [18F]1b or [18F]2b. (a) [18F]1b p.o.; (b) [18F]2b p.o.;
(c) [18F]1b i.v.; (d) [18F]2b i.v.; H, S, G, L, and D indicate heart,
stomach, gallbladder, liver, and duodenum, respectively.
To examine the intestinal absorption, distribution, and
excretion of each compound macroscopically, the PET/CT
images after administration of each PET tracer were compared
(SI Figure S2). In the case of intravenous injection, both tracers
initially moved into the heart, followed by the liver, and then
were distributed to the gallbladder and the duodenum. The
radioactivity in the kidney or the urinary bladder was markedly
lower than in the liver or gallbladder. These findings suggested
that both tracers are excreted mainly from the gallbladder,
rather than from the kidney. In the case of oral administration,
each compound was accumulated in the stomach first and then
moved to the duodenum. After intestinal absorption, the
compounds were distributed to the liver, moved to the
gallbladder, and excreted via the duodenum. The tracers were
still detected in the stomach at the end of the scanning period
(after 30 min). The radioactivity of each compound in the
kidney or urinary bladder was lower than in the gallbladder,
suggesting that these compounds are predominantly excreted
Figure S3). However, radioactivity (%ID) in the kidneys could
not be evaluated because the organ was located too close to the
stomach and duodenum. The %ID of [18F]2b at each organ
tended to be higher than that of [18F]1b by a ratio that was
proportional to the difference of blood concentration. In
particular, lung and muscle showed a marked difference in the
case of intravenous injection. Focusing on the %ID at the liver
after intravenous injection, [18F]1b gave a higher value than
[18F]2b, contrary to the order of blood concentration (Figure
4h). Since the compounds were administered at the same
dosage, [18F]1b was thought to migrate more easily to the liver
than [18F]2b. Measurement of radioactivity at the gallbladder
revealed that [18F]1b gave a significantly higher value than
[18F]2b, similarly to the case of liver after intravenous injection
(Figure 4e,f). Similar results were obtained with the [11C]
tracers (SI Figure S1). Thus, the difference of blood
concentration appears to be at least partly due to a difference
C
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ACS Medicinal Chemistry Letters
Letter
administration of each regioisomer was higher than that in the
lower digestive tract, and there was no difference between the
regioisomers. The reason for this may be inhibition of
peristaltic movement by anesthesia.20 Enterohepatic circulation
may also restrict transfer of the compounds to the lower
digestive tract.
Brain uptake of each tracer was observed by PET after
intravenous injection, as well as oral administration (Figure 4a,b
and SI Figure S1b). These results are similar to those reported
for [11C]bexarotene administered to a baboon, Papio anubis,15
though it is important to note that there are very likely to be
species differences in bexarotene behavior. The blood
concentrations of nonradioactive bexarotene, 1a, and 2a at 1
h after single oral administration of 30 mg/kg in 0.5% CMC
suspensions to mice were 4150, 1320, and 6760 ng/mL,
respectively (SI Table S1). The brain concentrations of
bexarotene and 1a were 1960 and 978 ng/mL, respectively,
whereas that of 2a is 2570 ng/mL. These results are consistent
with the PET analysis data. The brain-to-blood concentration
ratios of bexarotene, 1a, and 2a were 0.47, 0.74 and 0.38,
respectively. Although the brain concentration of bexarotene
seems lower than that reported by Landreth et al.,21 this may be
due to the different suspension formulations employed. Since
the lipophilicity of 1a is higher than that of 2a as shown by
HPLC and more lipophilic compounds can be transported
through the blood−brain barrier more easily, the above results
may reflect the differences of lipophilicity of the compounds.
However, since the blood concentration of 2a was higher than
that of 1a, more 2a was transported into the brain, as compared
to 1a.
In conclusion, PET imaging data revealed that 2a,b are
absorbed more easily from the digestive tract and excreted
more slowly than 1a,b. The brain concentrations of 2a,b were
markedly higher than those of 1a,b. Thus, the partial RXR
agonist 2a appears to be a promising candidate for the
treatment of Alzheimer’s and Parkinson’s diseases without the
serious side effects caused by RXR full agonists such as
bexarotene. Both compounds show predominantly biliary
excretion, which would be favorable in the treatment of
patients with impaired renal function.
Figure 4. Real-time changes in the ROI of the PET images with [18F]
1b (open or closed green circle) and [18F]2b (open or closed blue
squares). Time course of %ID (a) brain p.o., (b) brain i.v., (c) lung p.o.,
(d) lung i.v., (e) gallbladder p.o., (f) gallbladder i.v., (g) liver p.o., (h)
liver i.v., (i) stomach p.o., and (j) stomach i.v. were obtained from the
mean pixel radioactivity in ROI of the PET images acquired with
frames after the administration. Data shown are the average (n = 3−5)
SEM and analyzed by one-way ANOVA followed by t-test.
Significant differences: *p < 0.05, **p < 0.01 vs [18F]2b.
ASSOCIATED CONTENT
■
S
* Supporting Information
Supplementary in vitro and in vivo data. This material is
available free of charge via the Internet at http://pubs.acs.org.
of biliary excretion after hepatic metabolism. According to
Lipinsky’s rule, properties that would make a drug a likely
candidate for oral administration in humans include logP lower
than 5, because highly hydrophobic compounds tend to be
poorly absorbed after oral administration.19 The HPLC results
support the idea that 1a,b are less polar than 2a,b, and this may
influence the oral absorption. Moreover, the greater hydro-
phobicity of 1a,b than 2a,b may favor transfer to the liver and
biliary excretion. With both tracers, the %ID of the urinary
bladder is lower than that of the gallbladder, indicating that
these compounds are poorly excreted from the kidney (SI
Figure S2g,h). The predominant biliary excretion of these
compounds may make them good candidates for treatment of
patients with impaired renal function.
AUTHOR INFORMATION
■
Corresponding Author
*Tel/Fax: +81-(0)86-251-7963. E-mail: kakuta-h@cc.okayama-
u.ac.jp.
Author Contributions
H.K. conceived and designed the project. T.K. synthesized
compounds. T.K. and S.Y. performed reporter gene assays.
T.K., Y.F., and H.K. performed in vivo experiments. T.K., F.T.,
M.A., H.H., and H.K. synthesized PET tracers. T.S., A.A., and
T.H., performed PET scanning. T.K., A.T., and H.K. performed
HPLC analysis. The manuscript was written by T.K., E.M.,
A.T., and H.K.
Next, we compared the %ID values of the two compounds in
the stomach, upper digestive tract, and lower digestive tract
after oral administration (Figure 4i,j and SI Figure S2a−d). The
radioactivity in the stomach or upper digestive tract after oral
Funding
This work was supported by a subsidy to promote science and
technology in prefectures where nuclear and other power plants
D
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ACS Medicinal Chemistry Letters
Letter
moiety, NEt-3IP (RXRα/β-dual agonist). ChemMedChem 2008, 3,
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(11) Ohsawa, F.; Morishita, K.; Yamada, S.; Makishima, M.; Kakuta,
H. Modification at the lipophilic domain of RXR agonists differentially
influences activation of RXR heterodimers. ACS Med. Chem. Lett.
2010, 1, 521−525.
(12) Kawata, K.; Morishita, K.; Nakayama, M.; Yamada, S.;
Kobayashi, T.; Furusawa, Y.; Arimoto-Kobayashi, S.; Oohashi, T.;
Makishima, M.; Naitou, H.; Ishitsubo, E.; Tokiwa, H.; Tai, A.; Kakuta,
H. RXR partial agonist produced by side chain repositioning of alkoxy
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are located (to H.K.) from the Ministry of Education, Culture,
Sports, Science and Technology (MEXT) of Japan.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors are grateful to Prof. Yoshio Naomoto, Dr. Takuya
Fukazawa (Kawasaki Medical School), Dr. Kaori Endo-Umeda
(Nihon University), and Prof. Makoto Makishima (Nihon
University) for preparing plasmids. The authors are grateful to
the Division of Instrumental Analysis, Okayama University for
the NMR measurements.
(13) Bergstrom, M.; Grahnen, A.; Langstrom, B. Positron emission
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tomography microdosing: a new concept with application in tracer and
early clinical drug development. Eur. J. Clin. Pharmacol. 2003, 59,
357−366.
ABBREVIATIONS
■
E
(14) Fischman, A. J.; Alpert, N. M.; Rubin, R. H. Pharmacokinetic
imaging: a noninvasive method for determining drug distribution and
action. Clin. Pharmacokinet. 2002, 41, 581−602.
(15) Rotstein, B. H.; Hooker, J. M.; Woo, J.; Collier, T. L.; Brady, T.
J.; Liang, S. H.; Vasdev, N. Synthesis of [11C]bexarotene by Cu-
mediated [11C]carbon dioxide fixation and preliminary PET imaging.
ACS Med. Chem. Lett. 2014, 6, 668−672.
RXR, retinoid X receptor; PET, positron emission tomography;
max, maximum efficacy; EC50, half-maximal (50%) effective
concentration; p-TSA, p-toluenesulfonic acid; SEM, standard
error of the mean; ROI, region(s) of interest; SUV, standard
uptake values; EOB, end of bombardment; CMC, carbox-
ymethyl cellulose
(16) Van der Mey, M.; Janssen, C. G.; Janssens, F. E.; Jurzak, M.;
Langlois, X.; Sommen, F. M.; Verreet, B.; Windhorst, A. D.; Leysen, J.
E.; Herscheid, J. D. Synthesis and biodistribution of [(11)C]R116301,
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