The effect of aromatic fluorine substitution in L-DOPA on the in vivo behaviour of [18F]2-, [18F]5- and [18F]6-fluoro-L-DOPA in the human brain

Article abstract of DOI:10.1016/S0022-1139(02)00025-8

Remarkable differences in the human in vivo behaviour of each of the three [¹⁸F]-labelled ring fluorinated isomers of L-dihydroxyphenylalanine (L-DOPA) are presented. Unlike [¹⁸F]2-fluoro-L-DOPA, which did not appear to cross the blood brain barrier, [¹⁸F]5-fluoro-L-DOPA appears to be taken up and cleared from the cerebellum and the striata. In contrast with the 2- and 5-fluoro isomers of L-DOPA, radioactivity derived after injection of [¹⁸F]6-fluoro-L-DOPA is specifically retained in the striata. The present study is the first direct comparison of the time course and distribution of radioactivity in the human brain after intravenous injections of [¹⁸F]2-, [¹⁸F]5- and [¹⁸F]6-fluoro-L-DOPA.

Full text of DOI:10.1016/S0022-1139(02)00025-8

Journal of Fluorine Chemistry 115 (2002) 33–39
The effect of aromatic fluorine substitution in L-DOPA on the in vivo
18
18
18
behaviour of [ F]2-, [ F]5- and [ F]6-fluoro-L-DOPA
$
in the human brain
a,b,*
a
c
Raman Chirakal , Neil Vasdev , Marie-Claude Asselin ,
a
Gary J. Schrobilgen , Claude Nahmias
Department of Chemistry, McMaster University, Hamilton, Ont., Canada L8S 4M1
b,*
a
b
Department of Radiology, Faculty of Health Sciences, 1200 Main St. West, Hamilton, Ont., Canada L8N 3Z5
c
Department of Physics and Astronomy, McMaster University, Hamilton, Ont., Canada L8S 4M1
Received 12 December 2001; accepted 7 January 2002
Abstract
Remarkable differences in the human in vivo behaviour of each of the three [ F]-labelled ring fluorinated isomers of L-dihydroxyphe-
1
8
1
8
18
nylalanine (L-DOPA) are presented. Unlike [ F]2-fluoro-L-DOPA, which did not appear to cross the blood brain barrier, [ F]5-fluoro-L-
DOPA appears to be taken up and cleared from the cerebellum and the striata. In contrast with the 2- and 5-fluoro isomers of L-DOPA,
1
8
radioactivity derived after injection of [ F]6-fluoro-L-DOPA is specifically retained in the striata. The present study is the first direct
1
8
18
18
comparison of the time course and distribution of radioactivity in the human brain after intravenous injections of [ F]2-, [ F]5- and [ F]6-
fluoro-L-DOPA. # 2002 Elsevier Science B.V. All rights reserved.
Keywords: L-DOPA; Fluoro-L-DOPA; 18F; Brain uptake; Positron emission tomography
1
. Introduction
are associated with marked deficiencies of striatal dopamine
8]. These observations, corroborated many times by means
[
Medical applications of selectively fluorinated biomole-
of autopsy examinations [9], have led to the use of L-3,4-
dihydroxyphenylalanine (L-DOPA), the metabolic precursor
of dopamine, to alleviate the symptoms of Parkinson’s
cules have a long and successful history in medicinal
chemistry [1–3]. However, several physico-chemical prop-
erties are affected, and changes in biological activity occur
when fluorine is the substituent in a bioactive compound [4].
Kirk [5] has reviewed the pharmacological effects of several
selectively ring fluorinated catecholamines and shown that
different orientations of aromatic fluorine substitution can
display dramatic differences in pharmacological properties
from each other and their non-fluorinated derivatives. This
remarkable and unexpected phenomenon, which is depen-
dent on the site of the fluorine substituent, has been termed
the fluorine effect [6,7].
1
8
þ
disease [10]. A proposal that
F-(97% b , E
max
¼
0:635 MeV, t1=2 ¼ 109:7 min) labelled DOPA might be a
specific tracer for intracerebral dopamine inspired the synth-
1
8
esis of [ F]5-fluoro-DL-DOPA [11]. Following an intrave-
1
8
nous injection of [ F]5-fluoro-DL-DOPA in a monkey,
Garnett et al. [12] used simple g-ray detectors to monitor
F-activity. These authors used a three-compartment expla-
1
8
natory model to derive fractional rate constants for the
forward and backward transport of L-DOPA across the
blood–brain barrier, and for the formation and degradation
of neuronal dopamine. It was concluded that this technique
could be extended to man and used to investigate the role of
DOPA and dopamine in the control of mood and locomotion
It is known that the clinical features of Parkinson’s
disease, muscular rigidity, bradykinesia and rest tremor,
$
18
This work was presented in part at the 14th International Symposium
[12]. The lack of an efficient synthesis of [ F]5-fluoro-L-
on Radiopharmaceutical Chemistry, 10–15 June 2001, Interlaken, Switzer-
land.
DOPA had prevented it from being studied in the human
brain.
Subsequently, Garnett et al. [13] pioneered the use of
*
Corresponding authors. Tel.: þ1-905-521-2100x76893;
fax: þ1-905-546-1125.
[18
F]6-fluoro-L-DOPA, in conjunction with positron emission
tomography (PET), to visualize the regional distribution of
E-mail addresses: chiraklr@mcmaster.ca (R. Chirakal),
nahmias@mcmaster.ca (C. Nahmias).
0022-1139/02/$ – see front matter # 2002 Elsevier Science B.V. All rights reserved.
PII: S 0 0 2 2 - 1 1 3 9 ( 0 2 ) 0 0 0 2 5 - 8

34
R. Chirakal et al. / Journal of Fluorine Chemistry 115 (2002) 33–39
ꢁ
ꢁ
1
1
for [18F]5-fluoro-L-DOPA and
intracerebral dopamine in the living human brain. Fluorine-
8 labelled 6-fluoro-L-DOPA was further used to show that
0:0035 ꢀ 0:0019 min
0:0106 ꢀ 0:0019 min
18
1
for [ F]6-fluoro-L-DOPA (note
18
the accumulation of 18F was reduced in the contralateral
putamen of patients suffering from hemiparkinsonism [14].
These findings were the first demonstration of a disturbance
of intrastriatal dopamine metabolism in patients suffering
from Parkinson’s disease. Although the in vivo metabolism
the large uncertainty on the K value for [ F]2-fluoro-L-
i
1
8
DOPA). The very low uptake, if any, of [ F]2-fluoro-
dopamine in the brain confirms a previous report that
cerebral dopaminergic structures do not accumulate 18F
1
8
following injection of [ F]2-fluoro-L-DOPA [20]. The
18
1
8
of [ F]6-fluoro-L-DOPA in the human brain is known
15,16], the metabolic fate of 2- and 5-fluoro-DOPA in
the human brain has not been reported.
distribution and K values obtained with [ F]5-fluoro-L-
i
ꢁ1
18
[
DOPA (0:0030 ꢀ 0:0007 min ) and [ F]6-fluoro-L-DOPA
ꢁ
1
(0:0090 ꢀ 0:0005 min ) for subject 2 were similar to those
1
8
The fate of [ F]5-fluoro-L-DOPA in the human brain is
not known because low yielding Balz-Schiemann reactions
were the only methods described for its synthesis [11,17].
Recently, we have reported a reliable method for the pro-
for subject 1.
There are marked differences in the distribution and
kinetics of the three ring fluorinated isomers of L-DOPA.
1
8
For example, [ F]2-fluoro-L-DOPA does not appear to cross
18
18
duction of MBq quantities of [ F]5-fluoro-L-DOPA by the
direct fluorination of L-DOPA with [ F]F [18]. We have
the blood–brain barrier. In contrast, [ F]5-fluoro-L-DOPA
18
appears to be taken up and cleared from both the cerebellum
and striatum as indicated by the shape of the time-activity
curves. Fluorine-18 labelled 6-fluoro-L-DOPA clearly enters
the brain and shows that 18F preferentially accumulated in
the striata. The fluorine effect seen in our study is similar to
that seen in a previous study [21], which showed that the
substitution of fluorine for hydrogen at positions 2, 5 or 6 on
the aromatic ring of norepinephrine (NE) dramatically alters
the specificity of these analogues to their respective recep-
tors. The 2-fluoro-isomer of NE is a b-adrenergic agonist
with little a-activity, 6-fluoro-NE is an a-agonist with little
b-agonist activity, whereas, 5-fluoro-NE displays both a-
and b-adrenergic activity comparable to endogenous NE.
2
18
18
described the syntheses of [ F]2- and [ F]6-fluoro-L-
DOPA in earlier work [19]. We presently report a compara-
tive study of the time course and distribution of radioactivity
18
18
18
in the human brain after [ F]2-, [ F]5- and [ F]6-fluoro-L-
DOPA have been injected.
2
. Results and discussion
18
18
18
The distributions of [ F]2-, [ F]5-, and [ F]6-fluoro-L-
DOPA in a transaxial plane at the level of the striata in
subject 1 from 60 to 120 min after injection are shown in
18
18
18
Fig. 1. There is large accumulation of [ F]6-fluoro-dopa-
mine in the striata, whereas, there is a very small accumula-
tion of radioactivity in the grey matter and basal ganglia
The distribution of [ F]2- and [ F]6-fluoro-L-DOPA has
been studied in the carbidopa-pretreated male hooded rat
1
8
[22]. These authors showed that [ F]2-fluoro-L-DOPA is not
decarboxylated by the enzyme aromatic amino acid dec-
arboxylase (AADC, EC 4.1.1.26) in the rat striatum and is
rapidly O-methylated by the enzyme catechol-O-methyl-
transferase (COMT, EC 2.1.1.6). Although this study com-
18
18
following injection of [ F]2- and [ F]5-fluoro-L-DOPA.
18
18
18
The time courses of [ F]2-, [ F]5-, and [ F]6-fluoro-L-
DOPA for subject 1 are shown in Fig. 2. The striatal influx con-
stant (K ), using a cerebellar input function, was determined
i
to be 0:0027 ꢀ 0:0026 minꢁ for [ F]2-fluoro-L-DOPA,
1
18
18
18
pared the metabolism of [ F]2- and [ F]6-fluoro-L-DOPA,
Fig. 1. Distribution of [18F]2-fluoro-L-DOPA (left), [18F]5-fluoro-L-DOPA (middle), and [18F]6-fluoro-L-DOPA (right) in subject 1, 60–120 min after
intravenous injection of the tracer. The transaxial section, at the level of the basal ganglia, is at the same level in all three studies. The images have been
normalized to each other. Note the intense retention of radioactivity in the striata (darkest regions) following administration of [18F]6-fluoro-L-DOPA.

R. Chirakal et al. / Journal of Fluorine Chemistry 115 (2002) 33–39
35
Fig. 2. Time course of radioactivity in the striata (solid symbols) and the cerebellum (open symbols) after an intravenous injection of [18F]2-fluoro-L-DOPA
circles), [18F]5-fluoro-L-DOPA (squares), and [18F]6-fluoro-L-DOPA (diamonds).
(
these authors did not evaluate the metabolic fate of the 5-
fluoro isomer of L-DOPA. Several studies involving 5-
fluoro-DOPA have been conducted using racemic mixtures
of DL-DOPA, both in vitro [23–25] and in vivo [12,26,27].
Oldendorf [28] has shown that D-DOPA does not cross the
blood–brain barrier and in our laboratory, we did not observe
uptake of 18F in the striatum when a normal subject was
major role in understanding the biological imaging of the
1
8
dopaminergic pathway using [ F]-fluoro-L-DOPA [16,34].
In addition to transport across the blood–brain barrier, the
central availability of fluoro-L-DOPA is affected by periph-
eral metabolism. The enzymatic reaction rates are dependent
upon the availability of the substrate and their affinities for
AADC and COMT. The accumulation of fluorodopamine in
the striata is further dependent upon its ability to be stored in
vesicles within the nigrostriatial neurons, and its later release
along with endogenous dopamine [35].
1
8
injected with [ F]6-fluoro-D-DOPA [29]. Therefore, evalua-
tions of previous studies using 2-fluoro-DL-DOPA and 5-
fluoro-DL-DOPA are further complicated by the presence of
D-enantiomers. To our knowledge, only three studies, all of
which have been in vitro metabolic studies [30–32], have
Compared with L-DOPA, 2-fluoro-DOPA has a higher
affinity for COMT [24] and a substantially lower affinity for
AADC [22]. This suggests that 2-fluoro-L-DOPA is rapidly
O-methylated (at position 3) in the periphery, thereby
depleting the supply of 2-fluoro-L-DOPA to the brain. If
18
been reported evaluating [ F]5-fluoro-L-DOPA. Wiese et al.
25,31] have shown that 5- and 6-fluoro-DOPA enantiomers
reproducibly undergo O-methylation and that COMT inhi-
[
1
8
bitors may prove to be effective for PET application with
5
present in the brain, [ F]2-fluoro-L-DOPA would be further
O-methylated, leaving even smaller amounts available for
- and 6-fluoro-L-DOPA [32]. Although, these authors com-
1
8
pared the metabolism of 5- and 6-fluoro-L-DOPA, the meta-
bolism of the 2-fluoro isomer of L-DOPAwas not considered
in their studies.
enzymatic decarboxylation to [ F]2-fluoro-dopamine. To
our knowledge, no investigation has been carried out to
determine if 2-fluoro-dopamine can be stored within the
vesicles of the dopaminergic neurons. Alternatively, the very
Cross-species determinations of enzymatic activities in
F]6-fluoro-L-DOPA-PET studies are often equivocal
[18
low uptake of [ F]2-fluoro-L-DOPA in the brain could also
be attributed to its relatively poor transport across the blood–
brain barrier [22].
18
because in vitro determinations obtained from animal mod-
els and humans are substantially different [16,33]. Further-
more, a study comparing the 5- and 6-fluoro isomers of
DOPA also stated that cerebral metabolism cannot be exclu-
sively elucidated by in vitro enzyme assays [31]. Several
factors are involved in human in vivo studies that play a
In contrast with 2-fluoro-DOPA, it has been shown that 5-
fluoro-DOPA is comparable with L-DOPA as a substrate for
AADC [23], and 5-fluoro-L-DOPA crosses the blood–brain
barrier to an extent that is similar to that of L-DOPA [12].

36
R. Chirakal et al. / Journal of Fluorine Chemistry 115 (2002) 33–39
Interestingly, no evidence for substantial retention of
-fluoro-dopamine in the striatum was obtained in our study.
The affinity of 5-fluoro-DOPA for COMT was determined
in painful burns if not properly treated. Before beginning
work with HF, first aid-treatment procedures [44–46] should
be available and known to all laboratory personnel. Any
incident involving direct contact with anhydrous HF or its
aqueous solutions, the inhalation of HF gas or eye/skin
exposures to HF gas must be immediately treated and
brought to the attention of qualified medical personnel for
appropriate follow-up treatment.
5
to be higher than L-DOPA and comparable with that of
2
-fluoro-DOPA [24]. The increased phenolic ionization
produced by fluorine at the 5-position on the aromatic ring
of DOPA which, similar to 2-fluoro-DOPA, is situated ortho
to an activating hydroxyl group, likely promotes the forma-
tion of 4-O-methylated derivative [30]. The influence of
fluorine substitution on the site of enzymatic O-methylation
when fluorine is situated ortho to one of the phenolic groups
has also been noted for NE [36]. The relatively high affinity
4.1.1. Materials
18
Enriched [ O]O (18O, 95.87 at.%, Eurisotop, Saint
2
Aubin, France), neon (99.999%), anhydrous hydrogen fluor-
ide (Air Products), 1% F in neon (Canadian Liquid Air),
18
18
of COMT towards [ F]2- and [ F]5-fluoro-L-DOPA com-
pared with L-DOPA and [ F]6-fluoro-L-DOPA [37] com-
promises their utility as PET tracers. The use of a COMT
2
18
boron trifluoride, helium (99.9999%, Matheson), potassium
dihydrogenphosphate (Aldrich), b-3,4-dihydroxyphenyl-L-
alanine (Sigma), 3, 4-dihydroxyphenyl-acetic acid (Sigma),
glacial acetic acid (British Drug Houses), potassium acetate
(British Drug Houses), formic acid (British Drug Houses),
trifluoroacetic acid (Caledon) and HPLC grade acetonitrile
(Caledon) were used without further purification.
18
inhibitor may reveal specific uptake of [ F]5-fluoro-dopa-
mine in the striata, because 5-fluoro-DOPA was shown
to have an affinity towards AADC comparable with that
of L-DOPA [23].
The role of COMT cannot be solely responsible for the
fluorine effect when tracing in vivo dopaminergic function
with ring fluorinated isomers of L-DOPA. For example,
DeJesus and Mukherjee [38] have proposed 18F-labelled
derivatives of L-meta-tyrosine (FmT) as useful tracers for the
study of intracerebral dopamine metabolism. Because the
1
8
18
18
4.1.2. Syntheses of [ F]2-, [ F]5-, and [ F]6-fluoro-
L-DOPA
Fluorine-18 labelled F was produced by the 8O(p,n)18F
1
2
nuclear reaction using a Siemens RDS 112 proton–cyclotron
operating at 11 MeV and the ‘‘double shoot’’ method
[47,48]. Detailed reports on the synthesis and characteriza-
tion of 18F-labelled 2-, 5- and 6-fluoro-L-DOPA have been
published elsewhere [18,19].
1
8
peripheral metabolism of FmT is simpler than that of [ F]6-
1
8
fluoro-L-DOPA, [ F]6-FmT has been proposed as a superior
agent with which to study intracerebral metabolism in health
18
and disease in humans [39]. Unlike [ F]6-fluoro-DOPA,
FmT are not substrates for COMT since they lack the
necessary enediol moiety [40], but are substrates for AADC
1
8
18
4.1.3. Separation and purification of [ F]2-, [ F]5-,
1
8
[
41]. It has since been shown that the site of ring fluorination
on L-meta-tyrosine alters its biological properties, i.e.
[18F]6-FmT is superior for the assessment of dopamine
metabolism in the brain using PET, when compared with
and [ F]6-fluoro-L-DOPA
After fluorination of L-DOPA with [ F]F in a suitable
1
8
2
18
solvent, [ F]fluoro-L-DOPA was separated from the reac-
tion mixture using a reverse-phase HPLC column (Phenom-
enex M9 Partisil 10/50 ODS-3) and an aqueous solution of
[18
F]2-FmT [42] and [ F]4-FmT [43].
18
0.02 M KH PO (pH adjusted to 3.0–3.5 with 85% H PO )
containing 5% CH CN as the mobile phase, and was eluted
2 4 3 4
3
ꢁ
1
3
. Concluding remarks
at 3.5 ml min . The column eluate was monitored using a
UV detector (280 nm) and a Geiger-M u¨ ller counter (Bicron
SWGM B980C) coupled to a rate meter (Bicron Frik-
In the present study, the time course and distribution of
18
[18
18
brain are presented. Only [ F]6-fluoro-dopamine shows
F]2-, [ F]5-, and [ F]6-fluoro-L-DOPA in the human
Tech ). HPLC analysis of the reaction mixture gave one
TM
18
broad UV peak having the same retention time as L-DOPA
(14 min). The radiochromatograms of all samples showed
two major radioactive peaks having retention times between
14 and 17 min. Their identification has been described
1
8
specific accumulation in the striata, making [ F]6-fluoro-
L-DOPA the only useful ring-fluorinated isomer of L-DOPA
for the study of the dopaminergic pathway. This study
illustrates the importance of isomeric and radiochemical
purities in radiopharmaceutical design.
1
8
before [18]. The radiochemical yield of [ F]fluoro-L-DOPA
was determined as the ratio of 18F activity in the peaks
eluting at 14–17 min to the 18F activity in the reaction vessel.
The radioactive peaks were collected and evaporated to
dryness. The dry residue was redissolved in 0.5 ml of water
and the process was repeated two more times prior to further
purification. This was accomplished using a second reverse
phase HPLC column (Vydac C , 0:9 cm ꢂ 25 cm) with 0.1%
4
. Experimental
4
.1. General experimental procedures
1
8
Caution: Work with anhydrous HF is potentially hazar-
dous. Skin contact with even small amounts of HF can result
acetic acid in water as the mobile phase and an elution rate of
ꢁ
1
2.5 ml min . The radioactive peak eluting at 12–13 min

R. Chirakal et al. / Journal of Fluorine Chemistry 115 (2002) 33–39
37
Fig. 3. Radiochromatogram of: (a) the reaction mixture after radiofluorination of L-DOPA in HF/BF
and (c) [18F]6-fluoro-L-DOPA (B) after final purification (see Section 4.1.4 for HPLC conditions). Unlabelled peaks are unknown fluorine-containing species.
; (b) [18F]2-fluoro-L-DOPA (A) after final purification;
3
1
8
18
18
corresponded to [ F]2-, [ F]5- or [ F]6-fluoro-L-DOPA and
was collected for dose preparation.
isomer) was determined by passing an aliquot of the QC
sample through a reverse phase HPLC column (Vydac C ,
1
8
0
CH CN as the mobile phase and an elution rate of
2.5 ml min (Figs. 3 and 4). The eluate from the column
was passed through a Waters 490E Programmable Multi-
wavelength detector (280 nm) and Beckman Radioisotope
Detector (Model 170).
:9 cm ꢂ 25 cm) and 0.1% TFA in water containing 5%
4
.1.4. Dose preparation and quality control
3
1
8
18
18
ꢁ1
Pure [ F]2-, [ F]5- or [ F]6-fluoro-L-DOPA in 0.1%
acetic acid was collected in a pyrogen-free 10 ml vial and a
.1 ml sample was removed for quality control. Ascorbic
acid (ca. 1 mg) and 0.6 ml of 10% sodium chloride in water
0
18
(
sterile and pyrogen-free) were added and the [ F]fluoro-L-
DOPA solution was transferred through 0.22 mm sterile filter
Millipore Corporation, Bedford, MA) into a 10 ml sterile
4.2. PET scanning protocol
(
vial. Each batch passed quality control tests for pH (5–6),
sterility and pyrogenicity.
Two healthy, neurologically normal 55 year old subjects
participated in this study. The study was designed in accor-
dance with the Institutional Review Board, McMaster Uni-
versity. The subjects fasted for 4 h prior to the examination.
18
The radiochemical purity of [ F]fluoro-L-DOPA (96 ꢀ
% for 2- and 6- fluoro isomers and 91 ꢀ 4% for 5-fluoro
2

38
R. Chirakal et al. / Journal of Fluorine Chemistry 115 (2002) 33–39
Fig. 4. Radiochromatogram of: (a) the reaction mixture after radiofluorination of L-DOPA in glacial acetic acid containing 10% TFA, showing [18F]2-fluoro-
L-DOPA (A) and [18F]5-fluoro-L-DOPA (B); and (b) [18F]5-fluoro-L-DOPA after final purification (see Section 4.1.4 for HPLC conditions). Unlabelled peaks
are unknown fluorine-containing species.
They were not pretreated with carbidopa, as it has been
shown that this increases the radioactivity in the brain, but
not the specific accumulation in the striatum [49]. Subjects
were examined in an ECAT ART [50], after intravenous
Images were reconstructed using the reprojection algo-
rithm [51] and ramp filters at the Nyquist frequency. An
attenuation correction was calculated from a ‘‘singles’’
(137Cs) transmission scan acquired immediately prior to
the injection of the tracer [52]. The last 12 frames
(60 min) of the study were summed and regions of interest
(ROIs) were drawn with reference to a standard neuroana-
tomical atlas [53] around the right and left caudate nuclei,
the right and left putamina, and the cerebellum for the 6-
fluoro-L-DOPA study. These regions were then transferred to
the 2- and 5-fluoro-L-DOPA studies after careful re-align-
ment of the three studies based on the blood flow image (first
2 min of study summed). The decay-corrected time activity
curves in these ROIs were then obtained for the duration of
18
injection of between 110 and 185 MBq of [ F]5-, and
[18
F]6-fluoro-L-DOPA. Subject 1 was also injected with
50 MBq of [ F]2-fluoro-L-DOPA. Studies were conducted
1
8
1
within a 3-month interval. The head was immobilized in a
head holder and positioned so that the orbito-meatal line was
perpendicular to the axis of the gantry. Subjects were
scanned for 2 frames at 10 s per frame, 20 frames at 5 s
per frame, 6 frames at 10 s per frame, 4 frames at 180 s per
frame, and 21 frames at 300 s per frame for a total of
1
20 min.

R. Chirakal et al. / Journal of Fluorine Chemistry 115 (2002) 33–39
39
[
[
[
25] C. Wiese, M. Cogoli-Greuter, R. Weinreich, K.H. Winterhalter, J.
Neurochem. 58 (1992) 219–226.
the study. An influx constant (K ) [54] was calculated for
i
each of the regions using the cerebellum as the tissue
reference [55].
26] G. Firnau, E.S. Garnett, P.K.H. Chan, L.W. Belbeck, J. Pharm.
Pharmac. 28 (1976) 584–585.
27] E.S. Garnett, G. Firnau, P.K.H. Chan, S. Sood, L.W. Belbeck, Proc.
Natl. Acad. Sci. U.S.A. 75 (1978) 464–467.
[
28] W.H. Oldendorf, Am. J. Physiol. 224 (1973) 967–969.
29] E.S. Garnett, C. Nahmias, R. Chirakal, G. Firnau, unpublished
results.
Acknowledgements
[
We wish to thank Margo Thompson for her untiring
support and Dr. Shigeko Amano for helpful discussions.
N.V. and M.C.A. wish to thank the Natural Sciences and
Engineering Research Council of Canada for postgraduate
scholarships and the Christie Group Ltd. for awarding E.S.
Garnett Bursaries in Medical Imaging.
[
30] G. Firnau, S. Sood, R. Pantel, S. Garnett, Mol. Pharmacol. 19 (1980)
130–133.
[31] C. Wiese, M. Cogoli-Greuter, M. Argentini, T. Mader, R. Weinreich,
K.H. Winterhalter, Biochem. Pharmacol. 44 (1992) 99–105.
[
32] C. Wiese, M. Cogoli-Greuter, R. Weinreich, K.H. Winterhalter,
Naunyn-Schmiedeberg’s Arch. Pharmacol. 349 (1993) 582–585.
33] R.E. Yee, S.-C. Huang, D.B. Stout, I. Irwin, K. Shoghi-Jadid, D.M.
Togaski, L.E. DeLanney, J.W. Langston, N. Satyamurthy, K.F.
Farahani, M.E. Phelps, J.R. Barrio, J. Neurochem. 74 (2000) 1147–
[
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