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3. Gould, T. D.; Zarate, C. A.; Manji, H. K. J. Clin.
Psychiatry 2004, 65, 10.
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7. Wagman, A. S.; Johnson, K. W.; Bussiere, D. E. Curr.
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Blood
Cerebellum
0.900
0.800
Hippocampus
Striatum
Cortex
Hypothalamus
Thalamus
Rest
0.700
0.600
0.500
White matter
8. Bhat, R. V.; Budd Haeberlein, S. L.; Avila, J. J.
Neurochem. 2004, 89, 1313.
0.400
0.300
0.200
0.100
0.000
9. Gould, T. D.; Manji, H. K. Neuropsychopharmacology
2005, 1.
10. Meijer, L.; Flajolet, M.; Greengard, P. Trends Pharmacol.
Sci. 2004, 25, 471.
11. Bhat, R.; Xue, Y.; Berg, S.; Hellberg, S.; Ormo¨, M.;
Nilsson, Y.; Radesa¨ter, A.-C.; Jerning, E.; Markgren, P.-
˚
O.; Borgegard, T.; Nylo¨r, M.; Gimenez-Cassina, A.;
Hernandez, F.; Lucas, J. J.; Dıaz-Nido, J.; Avila, J. J.
´
´
´
0
5
10
15
20
25
30
Time (min)
Biol. Chem. 2003, 278, 45937.
12. Gould, T. D.; Einat, H.; Bhat, R.; Manji, H. K.
Int. J. Neuropsychopharmacol. 2004, 7, 387.
13. Greene, T. W.; Wuts, P. G. M. In Protective Groups in
Organic Synthesis, 2nd ed.; John Wiley & Sons: New
York, 1991, p 14.
14. Bhatt, M. V.; Kulkarni, S. U. Synthesis 1983, 249.
15. Learmonth, D. A.; Alves, P. C. Synth. Commun. 2002, 32,
641.
16. Forlani, L.; Todesco, P. E.. In Metzger, J. V., Ed.;
Thiazole and its Derivatives; John Wiley & Sons: New
York, 1979; Vol. 34, pp 565–585.
17. LC–MS was conducted by Electrospray Ionization using a
C-18 Zorbax column (50 mm · 2.1 mm, 3.5 lm) eluted
with CH3CN/H2O (40:60 v/v) + 0.5% formic acid using a
flow rate of 250 lL minꢀ1 in conjunction with a MDS
Sciex QStar mass spectrometer. A desmethyl AR-A014418
derivative with substitution at the thiazole moiety is
predicted based on the parent molecular ion for this
compound which showed a characteristic isotopic pattern
for monobromination, [M+H]: m/z = 328 and 330 (1:1).
The hydroxybenzyl moiety was seen at m/z = 107 in
addition to pairs of fragments corresponding to bromi-
nated thiazolamine, [M+H]: m/z = 179 and 181 (1:1). A
trace of dibrominated product was also seen, [M+H]:
m/z = 406, 408, and 410 (1:2:1), respectively, with both the
thiazole and benzyl fragments containing a bromine.
Time-course of this reaction revealed that bromination
at the thiazole occurs (<15 min) prior to demethylation
(ca. 1 h) therefore, this synthetic route was no longer
pursued.
Figure 1. Distribution of radioactivity in rat brain regions and whole
blood at 5 and 30 min (n = 6 per time point; means SD shown)
following tail vein injection of [11C]AR-A014418 is shown. Homoge-
neous distribution of low levels of radioactivity was seen in all brain
regions.
Figure 1 to 0.04% and 0.06% ID/g of wet tissue at 5
and 30 min, respectively. Thus, the brain is almost
totally impermeable to this compound (successful
radiotracers for imaging the central nervous system
typically express a % ID/g of tissue P0.5% in rodent
brain26).
Ex vivo measurement of radioactivity in tissue after
injection of [11C]AR-A014418 in rats clearly indicates
that this compound cannot be used to study GSK-3b
in the CNS with PET. The lack of brain penetration
of [11C]AR-A014418 is surprising considering that its
logP value between 1-octanol and 0.02 M phosphate
buffer at pH 7.4 was found to be 2.44, using a previously
described procedure,27 a value which is typical of many
brain penetrating compounds.27,28 The lack of brain
penetration is also surprising in light of reported CNS
effects following peripheral administration of AR-
A014418 into rats.12 Studies to investigate peripheral ef-
fects, metabolism and brain barrier transport of AR-
A014418 are presently underway in our laboratory and
hope to gain further insight into the pharmacological
mechanism(s) by which this compound could exert its
reported antidepressant-like effects.12
18. Schwartz, G.; Alberts, H.; Kricheldorf, H. R. Liebigs Ann.
Chem. 1981, 1257.
19. 4-[(Trimethylsilyl)oxy]-benzeneacetyl chloride was pre-
pared according to the literature procedure,18 however,
intermediates were not isolated; solvents were simply
removed by rotary evaporation proceeding each step and
the entire synthesis was successfully accomplished in one
pot. Azidotrimethylsilane (260 lL, 2.0 mmol) was added
to 4-[(trimethylsilyl)oxy]-benzeneacetyl chloride (400 mg,
1.65 mmol) in 1,4-dioxane (5 mL) and stirred at room
temperature for 2 h. Subsequently, 2-amino-5-nitrothiaz-
ole (440 mg, 3.0 mmol) was added and the mixture was
heated to reflux for 15 h. The resulting brown solution was
evaporated to dryness under a flow of nitrogen. The
residue was dissolved in EtOAc (ca. 100 mL) and washed
with 2 N HCl (3· 50 mL). The organic phase was dried
(Na2SO4), filtered, and concentrated prior to purification
by flash chromatography using silica gel (29% hexane, 69%
ethyl acetate, and 2% glacial acetic acid). Desmethyl
Acknowledgments
The Faculty of Medicine at the University of Toronto is
acknowledged for financial support for this work from
the DeanÕs Fund (N.V.). The authors thank Doug
Hussey, Patrick McCormick, and Hermia Cheung for
their expertise with the ex vivo evaluations.
References and notes
1. Woodgett, J. R. EMBO J. 1990, 9, 2431.
2. Grimes, C. A.; Jope, R. S. Prog. Neurobiol. 2001, 65, 391.