6-[123I]Iodo-2-[[4-(2-methoxyphenyl) piperazin-1-yl]methyl] imidazo[1,2-a]pyridine as potential SPECT agent for imaging dopamine D 4 receptor: Synthesis and in vivo evaluation in a nonhuman primate

Article abstract of DOI:10.1002/jlcr.1500

The dopamine O₄ receptor subtype has drawn considerable attention due to its potential implication in schizophrenia and erectile dysfunction. 6-[¹²³I]Iodo-2-[[4-(2-methoxyphenyl)piperazin-1-yl] methyl]imidazo[1,2-a]pyridine [¹²³

Full text of DOI:10.1002/jlcr.1500

Research Article
Received 31 October 2007,
Revised 15 January 2008,
Accepted 16 January 2008
Published online 12 March 2008 in Wiley Interscience
(www.interscience.wiley.com) DOI: 10.1002/jlcr.1500
6-[123I]Iodo-2-[[4-(2-methoxyphenyl)
piperazin-1-yl]methyl]imidazo[1,2-a]pyridine
as potential SPECT agent for imaging
dopamine D4 receptor: synthesis and in vivo
evaluation in a nonhuman primate
Ã
David Alagille,a Andrei O. Koren,a Greg Kudej,a Julie Staley,b
Kelly Cosgrove,b John Seibyl,a and Gilles D. Tamagnana
The dopamine D4 receptor subtype has drawn considerable attention due to its potential implication in schizophrenia and
erectile dysfunction. 6-[123I]Iodo-2-[[4-(2-methoxyphenyl)piperazin-1-yl]methyl]imidazo[1,2-a]pyridine [123I]-1, a potent and
selective new dopamine D4 agonist, was synthesized by classical iododestannylation using sodium [123I]iodide and
chloramine-T. Radiolabeling yield varied from 34 to 38% with a radiochemical purity exceeding 99%. Despite a good in vitro
profile, in vivo evaluation of this radioligand in baboon showed no brain uptake after i.v. injection.
Keywords: dopamine; D4; SPECT; schizophrenia; erectile dysfunction
some suggest a six-fold increase in the D4 receptor density in
schizophrenic patients compared with age-matched control;8,9
Introduction
Dopamine, a predominant catecholamine neurotransmitter in
the mammalian brain binds to two families of G-protein-coupled
receptors. Activation of receptors of the excitatory D1-like family
(D1 and D5 subtypes) is coupled to the G-protein Gas, which
activates adenylyl cyclase, whereas activation of members of the
inhibitory D2-like family (D2, D3, and D4 subtypes) is coupled to
the G-protein Gai, which increases phosphodiesterase activity.1–3
The dopamine D4 receptor subtype has drawn considerable
attention due to its potential implication in schizophrenia and
erectile dysfunction (ED). The classical dopamine hypothesis of
schizophrenia is based on the correlation between clinical doses
of antipsychotic drugs and their potency to antagonize the
dopamine D2 receptor.4 Antipsychotic drugs, however, manifest
a high level of side effects including extrapyramidal symptoms
(dystonia, parkinsonism, and tardive dyskinesia) and hyperpro-
lactinemia, which are presumably mediated by D2 receptors.5
The atypical antipsychotic clozapine, shown to be effective in
schizophrenic patients who are refractory to other neuroleptics,
displays a reduced risk of extrapyramidal symptoms.6 The
atypical pharmacological profile of clozapine was attributed to
its 10-fold greater affinity for the dopamine D4 receptor vs the
D2 subtype.7 The potential clinical importance of the D4 subtype
in schizophrenia has stimulated numerous attempts to evaluate
the density of these receptors in post-mortem schizophrenic
brain. The results of those studies are contradictory, whereas
others were unable to detect any D4 density variation in the two
populations.10,11 This discrepancy might be explained by the
indirect methodology used to determine the D4 density derived
by subtracting the number of binding sites identified with the
selective D2/D3 antagonist [3H]raclopride from the total number
binding sites associated with nonselective D2/D3/D4 antagonists
[3H]spiperone or [3H]nemonapride.
Another potentially important application of selective D4
agonists is the treatment of ED. Apomorphine, a nonselective
dopamine receptor antagonist, was clinically proven to be
effective medication for patients with ED.12,13 The erectogenic
effect of apomorphine may be attributable to its interaction
with the dopamine D4 receptor, whereas the dose-limiting side
effects (nausea and vomiting) are mediated via the D2
subtype.14–16
The lack of specific SPECT/PET imaging agents for in vivo
imaging of D4 receptor makes it difficult to fully understand its
aMolecular Neuroimaging, 60 Temple St, Suite 8A, New Haven, CT 06510, USA
bYale University School of Medicine, Psychiatry and Diagnostic Radiology, New
Haven, CT 06511, USA
*Correspondence to: David Alagille, Molecular Neuroimaging, 60 Temple St,
Suite 8A, New Haven, CT 06510, USA.
E-mail: dalagille@mnimaging.com
J. Label Compd. Radiopharm 2008, 51 202–206
Copyright r 2008 John Wiley & Sons, Ltd.

D. Alagille et al.
Figure 1. Examples of previously reported putative D4 radiotracers.
piperazin-1-yl]methyl]H-imidazo[1,2-a]pyridine core. Of particu-
lar interest in this series was the 6-iodo analogue 1 (Figure 2),
which was reported to have high affinity for the D4 receptor
(Ki = 0.33 nM) and good selectivity over the D1/D2/D3 subtypes.
Because D4 receptors are present in small densities in the brain
(6.5–25.5 fmol/mg),24 in vivo imaging of this receptor requires a
radiotracer with high affinity to obtain a reasonable binding
potential (BP = Bmax/KD). It is normally expected that to obtain
sufficient signal in vivo, the BP should exceed 0.5,25 which
implies in the case of D4 imaging, ligands require
a
Figure 2. Structure and binding profile (Ki, nM)23 of the target compound.
KDo3–12 nM. In the case of compound 1, KD is unknown (KD
is often in the same value range as Ki) but even with the
approximation of a KD 10 time superior to Ki for compound 1 the
resulting BP should be sufficient for imaging D4 receptors. We
therefore describe the synthesis of a trimethyltin precursor for 1,
the radiosynthesis of [123I]-1, and its in vivo evaluation in baboon
as potential D4 imaging agent.
involvement in both schizophrenia and ED. Over the past
decade, significant effort has been applied toward the devel-
opment of PET and SPECT radiotracer enabling in vivo imaging
of D4 receptors. A large structural variety of ligands with high
affinity for dopamine D4 receptors have been labeled and
studied without success in rodent, rabbit, and non-human
primate (Figure 1). In the 2-naphthoate series, [11C]SB-235753
shows low brain uptake, fast wash-out, and fast metabolic rate
with a uniform distribution within the brain.17 In the benzamide
series, although [11C]PB-12 shows promising results in rat brain
(specific cortical uptake), no specific binding in the monkey
brain was observed.18,19 In the chromen series, two tracers were
evaluated; [18F]FMTP shows specific uptake in rat frontal cortex
and medulla,20 but this study used cold FMTP as a self-blocking
agent and those results should be confirmed by use of known
displacing agents. [123I]ITCP shows brain uptake in rabbit, which
did not correlate the D4 distribution, and was not displaceable
by known D4 ligand.21 The azaindole [123I]L750,667 shows
uniform distribution within the monkey brain and is not
displaced by known D4 receptor antagonists at saturation
doses.22
Results and discussion
Chemistry
The synthesis of compound 3 was performed according to the
procedure developed by Enguehard-Gueiffier and coworkers23
(Scheme 1). The latter was converted into the stannylated
derivative 4 by the tetrakis(triphenylphosphine)palladium-cata-
lyzed reaction with excess of hexamethylditin. Finally, the iodo
compound 1 (used as a reference standard for the 123I-
radiolabeled product) was obtained by simple iodo-destannyla-
tion of 4 (Scheme 1).
Radiochemistry
123I]–1 was prepared by reaction of trimethylstannyl precursor 4
Recently, Enguehard-Gueiffier and coworkers23 described the
synthesis and structure–activity relationship of novel potent and
selective D4 partial agonists featuring a 2-[[4-(2-methoxyphenyl)-
[
with electrophilic [123I]iodine species generated in situ from
sodium [123I]iodide (Scheme 2). The reaction was carried out at
J. Label Compd. Radiopharm 2008, 51 202–206
Copyright r 2008 John Wiley & Sons, Ltd.
www.jlcr.org

D. Alagille et al.
Scheme 1
Scheme 2
room temperature using Chloramine-T as the oxidizing agent in detection at 254 nm. Purification of non-radioactive products
the presence of HCl. Purification by reverse-phase high- was achieved with flash column chromatography on silica gel
performance liquid chromatography (HPLC) with concomitant (240–400 mesh) or neutral aluminum oxide (150 mesh). Solvent
UV and radioactivity detection allowed identity confirmation of systems are indicated in the text. Nuclear magnetic resonance
[
[
123I]-1 by comparison to its corresponding unlabeled analog. (NMR) spectra were recorded at 400 MHz (1H) and 100 MHz (13C)
123I]-1 was obtained with a radiolabeling yield varying from 34 on a Bruker DPX 400 instrument with tetramethylsilane as
to 38% and was not optimized; the overall production yield internal standard. Yields refer to purified product and are not
averaged 27%. Radiochemical purity exceeded 99% with a optimized. No-carrier-added Na[123I]I was purchased from MDS-
specific activity above 185 GBq/mmol, based on the limits of Nordion (BC, Canada).
detection of the HPLC UV detector. Partition coefficient of [123I]-
1 was determined using the ‘shake-flask’ method26 at pH = 7.4.
The log D7.4 of 2.31 was in the range of values that is considered
Chemistry
acceptable for sufficient blood–brain barrier penetration.26,27
6-Bromo-2-(chloromethyl)imidazo[1,2-a]pyridine (2)23
2-Amino-5-bromopyridine (1 g, 1 eq) and 1,3-dichloroacetone
(734 mg, 1 eq) were dissolved in 3 mL of 1,2-dimethoxy ethane
(DME), and the resulting solution was stirred for 12 h at room
temperature. The formed white precipitate was filtered off,
washed with 1 mL of DME, redissolved in 10 mL of EtOH, and
refluxed for 2 h. The ethanol was evaporated, and the residue
was dissolved in 10 mL of water followed by adjusting pH to 11
with NaOH. The resulting precipitate was extracted with CH2Cl2,
dried over Na2SO4, concentrated in vacuum, and purified by
column chromatography on neutral aluminum oxide using
CH2Cl2 as an eluent. The intended product was obtained in 56%
(794 mg) yield as a white solid (m.p. = 125–1271C). NMR 1H
(CDCl3), d = 4.70 (s, 2H, CH2); 7.18 (dd, 1H, J = 9.6; 2.0 Hz, CHAr);
7.40 (d, 1H, J = 9.6 Hz, CHAr); 7.54 (s, 1H, CHAr); 8.17 (d, 1H,
J = 2.0 Hz, CHAr). NMR 13C (CDCl3), d = 39.7 (1C, CH2); 107.6 (1C,
Cq), 111.4 (1C, CHAr); 118.5 (1C, CHAr); 126.1 (1C, CHAr); 129.0
(1C, CHAr); 144.0 (1C, Cq); 144.2 (1C, Cq).
In vivo studies
The injection of 7.6 mCi of [123I]-1 through an intravenous
perfusion 0.9% saline line resulted in no detectable activity in
the brain during the 120-min scan acquisition. The overall low
availability of [123I]-1 to the central nervous system may be
attributable to the observed high degree of plasma protein
binding (97.5%) and/or to Pgp efflux. As the stability of [123I]-1
was not assessed, a fast metabolic rate could also explain the
absence of tracer in the brain.
Experimental
General
All chemicals and solvents were purchased from Sigma-Aldrich
and were used without further purification. Organic reactions
were monitored by thin layer chromatography with UV
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J. Label Compd. Radiopharm 2008, 51 202–206

D. Alagille et al.
6-Bromo-2-[[4-(2-methoxyphenyl)piperazin-1-yl]methyl]imidazo amount just enough to neutralize the NaOH), 50 mg of the
[1,2-a]pyridine (3)23
trialkylstannyl precursor 4 in 50 mL of methanol, and 50 mL of
chloramine-T trihydrate solution (1 mg/mL in water) were
To a solution of 2 (300 mg, 1 eq) in 2 mL of EtOH 1-(2-
added. After standing for 15 min at room temperature, the
methoxyphenyl)piperazine (243 mg, 1 eq) and K2CO3 (163 mg,
reaction mixture was quenched with 100 mL of Na2S2O5/NaHCO3
1 eq) were successively added. The resulting mixture was stirred
solution (100 mg Na2S2O5/mL NaHCO3 sat.) and injected onto a
at reflux for 4 h before evaporation of the solvent. The residue
reverse-phase HPLC column (Waters Nova-Pak C18,
was purified by chromatography on silica gel using a mixture of
4.6 Â 250 mm) eluted with a mixture of acetonitrile–water–-
CH2Cl2 and Et3N (99:1) as eluent. The title compound was
triethylamine (40:60:0.2 v/v/v) at a flow rate of 1 mL/min. The
obtained as a colorless oil in 70% (343 mg) yield. NMR 1H
fraction containing the target radiolabeled compound
(CDCl3), d = 2.63 (bs, 4H, 2CH2); 2.98 (bs, 4H, 2CH2); 3.64 (s, 2H,
(15.5–17 min) was diluted to a volume of 10 mL with water,
CH2); 3.68 (s, 3H, OCH3); 6.69 (d, 1H, J = 7.6 Hz, CHAr); 6.75–6.85
and the resulting solution was passed through a preconditioned
(m, 3H, CHAr); 7.02 (dd, 1H, J = 9.2; 1.6 Hz, CHAr); 7.29 (d, 1H,
solid-phase extraction cartridge (Waters Sep-Pak C18 Light). The
J = 9.2 Hz, CHAr); 7.35 (s, 1H, CHAr); 8.04 (d, 1H, J = 1.6 Hz, CHAr).
cartridge was then rinsed with 4 mL of 25% ethanol. The product
NMR 13C (CDCl3), d = 50.8 (2C, 2CH2); 53.7 (2C, 2CH2); 55.7 (1C,
retained on the cartridge was eluted with 0.9 mL of 100%
OCH3); 56.8 (1C, CH2); 107.0 (1C, Cq); 111.5 (1C, CHAr); 111.8 (1C,
ethanol into a sterile vial through a 0.2 mm sterilizing filter (Pall,
CHAr); 118.3 (1C, CHAr); 118.5 (1C, CHAr); 121.3 (1C, CHAr); 123.2
]4454). The formulation was finalized by the addition of 9 mL of
(1C, CHAr); 125.9 (1C, CHAr); 127.9 (1C, CHAr); 141.6 (1C, Cq);
sterile 0.9% NaCl for injection through the same filter. The
143.8 (1C, Cq); 144.8 (1C, Cq); 152.5 (1C, Cq).
radiolabeling yield varied from 34 to 38%, and the overall
production yield averaged 27%. Radiochemical purity and
chemical purity were assessed by HPLC in the same system,
with sequential gamma and UV detection, compared with a
standard of non-radioactive authentic 1. The radiochemical
2-[[4-(2-Methoxyphenyl)piperazin-1-yl]methyl]-6-trimethylstannyli-
midazo[1,2-a]pyridine (4)
In 2 mL of degassed DME, 3 (260 mg, 1 eq), hexamethylditin
purity exceeded 99% with a specific activity above 185 GBq/
(1.1 g, 5 eq), and Pd(PPh3)4 (74 mg, 0.1 eq) were dissolved
mmol. Quality control of the formulated product also included
visual inspection, determination of specific concentration, pH,
successively. The resulting mixture was refluxed for 5 h before
evaporation of the solvent under vacuum. The residue was
pyrogen content, and sterility. Sterility was confirmed by lack of
purified by chromatography on silica gel using a mixture of
growth in two media, fluid thioglycollate at 351C and soybean-
CH2Cl2 and Et3N (99:1) as eluent. The title compound was
obtained as a colorless oil at 71% (223 mg) yield. NMR 1H
(CDCl3), d = 0.05 (s, 9H, 3CH3); 2.49 (bs, 4H, 2CH2); 2.83 (4H,
2CH2); 3.50 (s, 2H, CH2); 3.52 (s, 3H, OCH3); 6.53 (d, 1H, J = 8.0 Hz,
CHAr); 6.59–6.68 (m, 3H, CHAr); 7.15 (dd, 1H, J = 8.0; 1.5 Hz,
CHAr); 7.25 (d, 1H, J = 8.0 Hz, CHAr); 7.37 (s, 1H, CHAr); 7.69 (d,
1H, J = 1.5 Hz, CHAr). NMR 13C (CDCl3), d = À8.9 (s, 3C, 3CH3); 50.9
(2C, 2CH2); 53.8 (2C, 2CH2); 55.6 (1C, OCH3); 57.0 (1C, CH2); 110.5
(1C, CHAr); 111.5 (1C, CHAr); 117.4 (1C, CHAr); 118.5 (1C, CHAr);
121.3 (1C, CHAr); 123.1 (1C, CHAr); 128.9 (1C, CHAr); 130.4 (1C,
Cq); 132.4 (1C, CHAr); 141.8 (1C, Cq); 143.4 (1C, Cq); 145.3 (1C,
Cq); 152.6 (1C, Cq).
casein digest at 251C for 2 weeks. Partition coefficient was
determined using published methods.26 Briefly, from stock
solutions of 1-octanol and 0.02 M phosphate buffer (pH = 7.4)
pre-saturated with each other, 2 mL of each was pipetted into a
12 mL test tube containing 10 mL of radiotracer. The test tube
was stoppered, vigorously vortexed for 10 min, and centrifuged
for 5 min at 4000 rpm. Aliquots (0.5 mL) of both organic and
buffer layers were transferred into a pre-weighed test tube for
counting. The amount of radioactivity in each tube was
measured by g counter and corrected for decay. Accurate
volumes of each counted phase were determined by weight
differences and known densities. The partition coefficient was
calculated, and the reported value log D7.4 = 2.31 represents the
mean of three measurements.
6-Iodo-2-[[4-(2-methoxyphenyl)piperazin-1-yl]methyl]imidazo[1,2-
a]pyridine (1)
To a solution of 4 (100 mg, 1 eq) in 5 mL of CH2Cl2 I2 (58 mg,
1.1 eq) was added, and the resulting mixture was stirred
at room temperature for 30 min. The solvent was evaporated
and the residue purified by chromatography on silica gel using
a mixture of CH2Cl2 and Et3N (99:1) as eluent. The target
compound was obtained as a colorless oil in 89% (82 mg) yield .
NMR 1H (CDCl3), d = 2.71 ((bs, 4H, 2CH2); 3.06 (bs, 4H, 2CH2); 3.71
(s, 2H, CH2); 3.77 (s, 3H, OCH3); 6.77 (d, 1H, J = 8.0 Hz, CHAr);
6.83–6.91 (m, 3H, CHAr); 7.20 (dd, 1H, J = 9.0; 2.0 Hz, CHAr); 7.28
(dd, 1H, J = 9.0; 2.0 Hz, CHAr); 7.42 (d, 1H, J = 2.0 Hz, CHAr); 8.24
(s, 1H, CHAr).
In vivo SPECT imaging
Baboon SPECT imaging was carried out as previously de-
scribed22 under institutional animal-care protocols complying
with Federal regulations. A single female baboon (ovariecto-
mized Papio anubis, 20 kg) was fasted for 18–24 h before the
study. At 2 h before injection, the animal was anesthetized with
intramuscular ketamine (10 mg/kg) and glycopyrrolate (0.01 mg/
kg), transferred to the SPECT camera, and immediately
intubated with an endotracheal tube for continued anesthesia
with 2.5% isoflurane. The baboon’s head was immobilized
within the gantry with a ‘bean bag’ that hardens upon
evacuation (Olympic Medical, Seattle, WA, USA). Body tempera-
ture was kept at 36.470.31C using a heated water blanket. Vital
signs, including heart rate, respiration rate, oxygen saturation,
and body temperature, were monitored every 15 min during the
study. An intravenous perfusion line with 0.9% saline was placed
Radiochemistry
6-[123I]Iodo-2-[[4-(2-methoxyphenyl)piperazin-1-yl]methyl]imida-
zo[1,2-a]pyridine ([123I]-1)
To a 1 mL serum-stoppered cone V vial as provided by the and used for a single bolus injection of the radiolabeled
vendor containing Na[123I]I and NaOH, 1.0 M HCl (20 mL over the compound [123I]-1.
J. Label Compd. Radiopharm 2008, 51 202–206
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D. Alagille et al.
[9] P. Seeman. H. C. Guan, H. H. Van Tol, Nature 1993, 365, 441–445.
[10] G. P. Reynolds, S. L. Mason, J. Neurochem. 1994, 63, 1576–1577.
[11] G. P. Reynolds, S. L. Mason, Eur. J. Pharmacol. 1995, 281, R5–R6.
[12] K. E. Andersson, Pharmacol. Rev. 2001, 53, 417–450.
[13] M. Zarrindast, S. Shokravi, M. Samini, Gen. Pharmacol. 1992, 23,
671–675.
SPECT data acquisition
SPECT data were acquired with a brain-dedicated multislice
CERASPECT camera (Digital Scintigraphics, Waltham, MA, USA)
with a resolution in all three axes of approximately 12 mm full-
width half-maximum measured using an 123I line source and a
20-cm water-filled cylindrical phantom. The distribution of
radioactivity was assessed after administration of a single
injected bolus of 7.6 mCi. Brain images (128 Â 128 Â 64 matrix,
pixel size = 1.67 Â 1.67 mm, slice thickness = 1.67 mm, voxel
volume = 4.66 mm3) were acquired at 159 keV in step-and-shoot
mode at 15 min each, for a total of 120 min and eight
acquisitions.
[14] J. D. Brioni, R. B. Moreland, M. Cowart, G. C. Hsieh, A. O. Stewart,
P. Hedlund, D. L. Donnelly-Roberts, M. Nakane, J. J. Lynch,
T. Kolasa, J. S. Polakowski, M. A. Osinski, K. Marsh, K. E. Andersson,
J. P. Sullivan, Proc. Natl. Acad. Sci. USA 2004, 101, 6758–6763.
[15] G. C. Hsieh, P. R. Hollingsworth, B. Martino, R. Chang, M. A.
Terranova, A. B. O’Neill, J. J. Lynch, R. B. Moreland, D. L. Donnelly-
Roberts, T. Kolasa, J. P. Mikusa, J. M. McVey, K. C. Marsh, J. P.
Sullivan, J. D. Brioni, J. Pharmacol. Exp. Ther. 2004, 308, 330–338.
[16] M. V. Patel, T. Kolasa. K. Mortell, M. A. Matulenko, A. A. Hakeem,
J. J. Rohde, S. L. Nelson, M. D. Cowart, M. Nakane, L. N. Miller,
M. E. Uchic, M. A. Terranova, O. F. El-Kouhen, D. L. Donnelly-
Roberts, M. T. Namovic, P. R. Hollingsworth, R. Chang, B. R. Martino,
J. M. Wetter, K. C. Marsh, R. Martin, J. F. Darbyshire, G. Gintant,
G. C. Hsieh, R. B. Moreland, J. P. Sullivan, J. D. Brioni, A. O. Stewart,
J. Med. Chem. 2006, 49(25), 7450–7465.
[17] M. Matarrese, D. Soloviev, R. M. Moresco, S. Todde, P. Simonelli, D.
Colombo, F. Magni, A. Carpinelli, F. Fazio, M. G. Kienle, J Label.
Compd. Radiopharm. 2000, 43(4), 359–374.
[18] O. Langer, C. Halldin, Y. H. Chou, J. Sandell, C. G. Swahn, K. Nagren,
R. Perrone, F. Berardi, M. Leopoldo, L. Farde, Nucl. Med. Biol. 2000,
27(8), 707–715.
[19] M. R. Zhang, T. Haradahira, J. Maeda, T. Okauchi, K. Kawabe,
J. Noguchi, T. Kida, K. Suzuki, T. Suhara, Nucl. Med. Biol. 2002, 29(2),
233–241.
[20] H.-B. Tian, D.-Z. Yin, L. Zhang, L.-H. Wang, C.-F. Zhang, M.-W. Wang,
C.-Y. Wu, G.-C. Li, Y.-X. Wang, Appl. Radiat. Isot. 2005, 63(3),
333–342.
Conclusion
6-[123I]Iodo-2-[[4-(2-methoxyphenyl)piperazin-1-yl]methyl]imida-
zo[1,2-a]pyridine 1 can be readily prepared from the corre-
sponding trimethylstannyl precursor and commercially available
sodium [123I]iodide. The compound displays high binding
affinity and selectivity for the D4 dopamine receptor, adequate
lipophilicity, and moderately elevated free parent fraction in
blood plasma. However, in vivo evaluation of this radioligand
showed no brain uptake in baboon (P. anubis) after i.v. injection.
This outcome indicates that the studied compound is not
suitable for imaging D4 dopamine receptor in vivo.
References
[21] L. Staelens, R. Oltenfreiter, P. Blanckaert, V. Kersemans,
K. Vandenbulcke, C. Van De Wiele, G. Slegers, Nucl. Med. Biol.
2005, 32(3), 293–299.
[22] J. K. Staley, G. D. Tamagnan, R. M. Baldwin, M. Fujita, M. S. Al Tikriti,
L. Eshima, J. Thornback, D. Roe, L. Lu, J. P. Seibyl, R. B. Innis, Nucl.
Med. Biol. 2000, 27(6), 547–556.
[1] C. Missale, S. R. Nash, S. W. Robinson, M. Jaber, M. G. Caron, Physiol.
Rev. 1998, 78, 189–225.
[2] P. Seeman, H. H. M. Van Tol, Trends Pharmacol. Sci. 1994, 15(7),
264–270.
[23] C. Enguehard-Gueiffier, H. Huebner, A. El Hakmaoui, H. Allouchi,
P. Gmeiner, A. Argiolas, M. R. Melis, A. Gueiffier, J. Med. Chem.
2006, 49(13), 3938–3947.
[24] F. I. Tarazi, N. S. Kula, R. J. Baldessarini, NeuroReport 1997, 8,
3423–3426.
[3] D. S. Hartman, O. Civelli, Prog. Drug. Res. 1997, 48, 173–194.
[4] I. Creese, D. Burt, S. Snyder, Science 1976, 192, 481–483.
[5] R. J. Baldessarini, D. Tarsy, Annu. Rev. Neurosci. 1980, 3, 23–41.
[6] R. J. Baldessarini, F. R. Frankenburg, N. Eng. J. Med. 1991, 324(11),
746–754.
[25] M. Laruelle, M. Slifstein, Y. Huang, Mol. Imaging Biol. 2003, 5(6),
363–375.
[26] A. A. Wilson, L. Jin, A. Garcia, J. N. DaSilva, S. Houle, Appl. Radiat.
Isot. 2001, 54(2), 203–208.
[27] R. N. Waterhouse, Mol. Imaging Biol. 2003, 5(6), 376–389.
[7] H. H. M. Van Tol, J. R. Bunzow, H.-C. Guan, R. K. Sunahara, P.
Seeman, H. B. Niznik, O. Civelli, Nature 1991, 350(18 April),
610–614.
[8] P. Seeman, H. C. Guan, H. H. Van Tol, Eur. J. Pharmacol. 1995, 286,
R3–R5.
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