Discovery of N-{(1S,2S)-2-(3-cyanophenyl)-3-[4-(2-[18F] fluoroethoxy)phenyl]-1-methylpropyl}-2-methyl-2-[(5-methylpyridin-2-yl)oxy] propanamide, a cannabinoid-1 receptor positron emission tomography tracer suitable for clinical use

Article abstract of DOI:10.1021/jm070131b

The discovery of a structurally distinct cannabinoid-1 receptor (CB1R) positron emission tomography tracer is described. Starting from an acyclic amide CB1R inverse agonist (1) as the lead compound, an efficient route to introduce ¹⁸F to the mo

Full text of DOI:10.1021/jm070131b

J. Med. Chem. 2007, 50, 3427-3430
3427
Discovery of N-{(1S,2S)-2-(3-Cyanophenyl)-
3-[4-(2-[18F]fluoroethoxy)phenyl]-1-methylpropyl}-
2-methyl-2-[(5-methylpyridin-2-yl)oxy]propan-
amide, a Cannabinoid-1 Receptor Positron
Emission Tomography Tracer Suitable for
Clinical Use
Figure 1. Representative examples of CB1R PET or SPECT tracers.
Scheme 1. Substrates for Attempted Fluoride Exchange
Ping Liu,*,† Linus S. Lin,† Terence G. Hamill,‡
James P. Jewell,†,# Thomas J. Lanza, Jr,†
Raymond E. Gibson,‡ Stephen M. Krause,‡ Christine Ryan,‡
Waisi Eng,‡ Sandra Sanabria,‡ Xinchun Tong,†
Junying Wang,† Dorothy A. Levorse,† Karen A. Owens,†
Tung M. Fong,§ Chun-Pyn Shen,§ Julie Lao,§
Sanjeev Kumar,| Wenji Yin,| Joseph F. Payack,∞
Shawn A. Springfield,∞ Richard Hargreaves,‡
H. Donald Burns,‡ Mark T. Goulet,†,# and
William K. Hagmann†
Departments of Medicinal Chemistry, Metabolic Disorders, Drug
Metabolism, and Process Research, Merck Research Laboratories,
Rahway, New Jersey 07065, and Department of Imaging Research,
Merck Research Laboratories, West Point, PennsylVania 19486
Scheme 2. Alkylation of Phenol 6a
ReceiVed February 2, 2007
Abstract: The discovery of a structurally distinct cannabinoid-1
receptor (CB1R) positron emission tomography tracer is described.
Starting from an acyclic amide CB1R inverse agonist (1) as the lead
compound, an efficient route to introduce 18F to the molecule was
developed. Further optimization focused on reducing the lipophilicity
and increasing the CB1R affinity. These efforts led to the identification
of [18F]-16 that exhibited good brain uptake and an excellent signal-
to-noise ratio in rhesus monkeys.
a Inhibition of binding (mean ( SD, n g 4 independent experiments) of
[3H]CP-55940 to recombinant human CB1 receptors expressed on Chinese
hamster ovary cells.13 b HPLC log D (pH 7.3).
Cannabinoid receptors belong to the superfamily of G-protein-
coupled receptors. Cannabinoid-1 receptors (CB1R) are mainly
located within the central nervous system, and cannabinoid-2
receptors (CB2R) are mainly associated with cells of the immune
system.1 Cannabinoid receptors are recognized for mediating
their biological effects through exposure to agonists, antagonists,
or inverse agonists. While CB1R agonists are known to be
beneficial for the treatment of pain, chemotherapy-induced
nausea, and emesis,2 CB1R antagonists or inverse agonists may
be beneficial for the treatment of smoking cessation,3 appetite
control,3 and other central nervous system disorders.4 Currently,
rimonabant, a selective CB1R inverse agonist from Sanofi-
Aventis, has been approved in the European Union and is under
FDA review as a novel treatment for obesity. To better
understand CB1R biology and assist in the design and testing
of promising drug candidates targeting this receptor, a suitable
CB1R positron emission tomography (PET) or single photon
emission computed tomography (SPECT) radioligand is highly
desirable that would allow CB1R imaging studies in the living
human and animal brain under normal physiological and
diseased conditions. In general, a successful PET ligand should
provide a good specific signal (total/nonspecific, g2:1) to allow
quantitative mapping of a receptor of interest. Ideally, a brain
PET ligand needs to have a good affinity with Bmax/Kd g 10
and reasonable lipophilicity with log P or log D ≈ 1-3.5 for
adequate brain penetration and optimum specific to nonspecific
ratio.5,6 Much effort has been devoted to the search for suitable
CB1R PET and SPECT ligands. Most of the reported radioli-
gands are variations of alkylindoles7 or 1,5-diaryl-3-carboxy-
pyrrazoles, for example, [18F]-AM694,8 123I]-AM281,9 and
[
[11C]-JHU7552810 (Figure 1). Although progress has been made
in this area, PET imaging studies of CB1R have been unsatis-
factory presumably because of low affinity and/or high lipo-
philicity of the previous ligands. Herein, we report the discovery
of a novel CB1R PET tracer (MK-9470) that has proven suitable
for clinical application.11
The medicinal chemistry efforts began with taranabant (MK-
0364), a potent CB1R inverse agonist (1) that had been selected
for clinical evaluation to treat obesity.12 Compound 1 has an
HPLC log D value of 5.2 and human CB1R IC50 of 0.3 nM.
Although the lipophilicity of 1 is higher than desired, we were
encouraged by its excellent CB1R affinity. We decided to direct
our initial effort to finding a reliable route to introduce a
radiolabel before addressing the lipopholicity issue of the lead.
Exchange of a fluorine atom of the trifluoromethyl group in
1 with 18F was first attempted. However, the substrate 1 and
the bromo precursor 214 (Scheme 1) failed to produce the high
specific activity required for a receptor based PET tracer.
Introduction of 18F onto one of the phenyl rings was then
investigated because labeling of a 3-fluorobenzonitrile was
* To whom correspondence should be addressed. Phone 732-594-0321.
Fax 732-594-5966. E-mail: ping_liu2@merck.com.
† Department of Medicinal Chemistry, Merck, NJ.
‡ Department of Imaging Research, Merck, PA.
# Current affiliation: MRL Boston.
§ Department of Metabolic Disorders, Merck, NJ.
| Department of Drug Metabolism, Merck, NJ.
∞ Department of Process Research, Merck, NJ.
10.1021/jm070131b CCC: $37.00 © 2007 American Chemical Society
Published on Web 07/03/2007

3428 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 15
Letters
Table 1. Inhibition of CB1R (IC50, nM)a and HPLC log D of
Fluoroethyl Analogues
Figure 2. Metabolic stability of 16 (top) and 10 (bottom) in liver
microsomes (0.2 mg protein/mL, 1 µM substrate) in rats, monkeys,
and humans. Values are the average of three determinations.
noticeable log D reduction was observed when the 5-CF3 group
was replaced with H (12) or CN (14) or when an additional
nitrogen atom was introduced to the pyridine ring to derive the
corresponding pyrimidine (17). However, some loss of CB1R
binding activity was also observed in these cases. Replacement
of 5-CF3 with 5-CH3 resulted in an improvement over 10 in
log D and CB1R affinity (16). Again, moving 5-CH3 to 4-CH3
provided no advantage in potency or lipophilicity (16 vs 15).
Overall, analogue 16 appeared to offer the best balance of CB1R
affinity (IC50 ) 0.7 nM) and liphophilicity in this series.
Therefore, this compound was selected for further characteriza-
tion.
a Inhibition of binding (mean ( SD if n g 4 independent experiments;
individual values if n ) 2).13 b HPLC log D (pH 7.3).
successful in a previous program.15 The SAR study suggested
that the Y position of the top phenyl ring (Scheme 1) could be
substituted by fluorine because the fluoro analogue exhibited a
very high human CB1R binding affinity (IC50 ) 0.1 nM).
However, when the bromo or chloro precursor 3 or 4 was
subjected to nucleophilic substitution with fluoride, no desired
product was observed presumably because of insufficient
activation of the phenyl ring by the nitrile group.
Finally, alkylation of a phenolic precursor with radiolabeled
electrophiles was evaluated. Palladium catalyzed boronation of
aryl chloride 5 afforded a boronic ester that was subsequently
oxidized to phenol 6.16 The appropriate electrophile was reacted
with 6 to afford the ethers 7-9 (Scheme 2). On the basis of the
CB1R binding data, the methoxy analogue 7 and the fluoroet-
hoxy analogue 9 were potential candidates as PET ligands.
Furthermore, of the three analogues, the fluoroethoxy analogue
9 seemed to be the least lipophilic with the lowest log D. For
the radiolabeled 9 where R is 18FCH2CH2, specific activity of
>1000 Ci/mmol was achieved.11a Therefore, further exploration
of the physical properties of 9 was pursued with the objective
of lowering lipophilicity while maintaining potency.
Compound 16 is a selective CB1R inverse agonist with
human CB2R IC50 of 44 nM. Other off-target activities of 16
were evaluated in 168 assays of receptors, enzymes, ion
channels, and transporters, and it showed more than 700-fold
selectivity over all the targets tested. This compound was not a
substrate for mouse (Mdr1a) or human (MDR1) P-glycoprotein
in vitro and rapidly penetrated into the brain and achieved a
brain-to-plasma concentration ratio of 0.5 at 15 min after a 1
mg/kg iv dose to rats.
Compound 16 exhibited high clearance (81 mL min-1 kg-1
)
and short half-life (1.4 h) in rats following a 1 mg/kg iv dose.
In vitro metabolism studies of 16 were carried out in liver
microsomes from rats, monkeys, and humans. As illustrated in
Figure 2, 16 is much more stable in human liver microsomes
than in rat and monkey microsomes, which suggested that [18F]-
16 may be cleared more slowly in humans. Interestingly,
analogous studies with the CF3 analogue 10 demonstrated that
it is metabolized much more quickly than 16 in human liver
microsomes, although they behave similarly in liver microsomes
of rats and monkeys.
Deletion of the fluorine from the phenyl ring of 9 afforded
10 with a slightly lower log D (4.4 vs 4.6, Table 1) while
retaining the same level of affinity. The amine portion of the
molecule was then conserved, and SAR efforts focused on
modification of the right-hand portion of the molecule.
As shown in Table 1, moving the CF3 group from the
5-position to the 4-position (11) or replacement of CF3 with Cl
(13) did not lead to improvement in log D or CB1R potency. A
In general, the CF3 group is metabolically more stable than
the CH3 group; however replacement of CH3 with CF3 in this
case did not lead to a more stable structure presumably because
of increased lipophilicity and binding to the CYP enzymes.

Letters
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 15 3429
Scheme 3. Synthesis of the PET Tracer [18F]-16a
carried out with the CB1R inverse agonist 1 and the total to
nonspecific signal ratio was ∼5:1 in one subject and ∼4:1 in
another, exceeding the targeted criteria (2:1) for a PET tracer.
The properties of this PET tracer are summarized in Figure 3.
To our knowledge, [18F]-16 demonstrated the best profile among
the CB1R tracers reported thus far.22
In summary, a high-affinity inverse agonist CB1R PET tracer
[18F]-16 was identified by the development of a suitable
radiolabeling route and optimization of potency and lipophilicity.
This tracer exhibited good brain uptake and an excellent signal-
to-noise ratio (total/nonspecific, 4 to 5:1) in rhesus monkey PET
studies. The clinical results of [18F]-16 will be the subject of
another publication.11b
Acknowledgment. The authors acknowledge the contribu-
tions of Drs. Scott Hoerrner, James McNamara, Raymond Evers,
and Kerry Riffel.
Supporting Information Available: Experimental procedures
and characterization data for all new compounds; detailed descrip-
tion of pharmacological assays, in vitro metabolism protocol, and
rhesus PET imaging studies. This material is available free of charge
via the Internet at http://pubs.acs.org.
a Reagents and conditions: (a) Boc2O, PhMe, 94%; (b) bis(pinacolato-
)diboron, Pd2(dba)3, PCy3, KOAc, dioxane, 90-92 °C; (c) Oxone, NaHCO3/
NaOH, acetone/THF/H2O (1:1:1, v/v/v), 0 °C, 95% for two steps; (d) HCl/
dioxane, 100%; (e) ethyl 2-bromoisobutyrate, Cs2CO3, MeCN, 50 °C; (f)
NaOH, H2O/MeCN, 50 °C, 52% for two steps; (g) EDC, pyridine, MeCN,
50 °C, 85%; (h) [18F]-FCH2CH2Br, Cs2CO3, DMF, 100 °C.
References
(1) Howlett, A. C.; Barth, F.; Bonner, T. I.; Cabral, G.; Casellas, P.;
Devane, W. A.; Felder, C. C.; Herkenham, M.; Mackie, K.; Martin,
B. R.; Mechoulam, R.; Pertwee, R. G. International Union of
Pharmacology. XXVII. Classification of cannabinoid receptors.
Pharmacol. ReV. 2002, 54, 161-202.
(2) Grotenhermen, F. Pharmacokinetics and pharmacodynamics of can-
nabinoids, Clin. Pharmacokinet. 2003, 42, 327-360.
(3) Arnone, M.; Maruani, J.; Chaperon, F. Selective inhibition of sucrose
and ethanol intake by SR141716a, an antagonist of central cannab-
inoid receptors. Psychopharmacology 1998, 132, 104-106.
(4) Van der Stelt, M.; Fox, S. H.; Hill, M.; Crossman, A. R.; Petrosino,
S.; Di Marzo, V.; Brotchie, J. M. A role for endocannabinoids in the
generation of Parkinsonism and levodopa-induced dyskinesia in
MPTP-lesioned non-human primate models of Parkinson’s disease.
FASEB J. 2005, 19, 1140-1142.
(5) Eckelman, W. C.; Gibson, R. E.; Rzeszotarski, W. J.; Vieras, F.;
Mazaitis, J. K.; Francis, B.; Reba, W. C. The Design of Receptor
Binding Radiotracers. In Principles of Radiopharmacology; Colom-
betti, L. G., Ed.; CRC Press: New York, 1979; Vol. 1, pp 251-
274.
Figure 3. Profile of [18F]-16 and its in vivo PET images in rhesus
monkey brain. Color scale indicates SUV units.
(6) Waterhouse, R. N. Determination of lipophilicity and its use as a
predictor of blood-brain barrier penetration of molecular imaging
agents. Mol. Imaging Biol. 2003, 5, 376-389.
The synthesis of [18F]-16 is outlined in Scheme 3 and began
with the enantiomerically pure amine 1812,21 that was reacted
with Boc2O to give Boc-protected amine 19. The key transfor-
mation of this synthetic sequence was the conversion of the
chlorobenzene moiety in 19 to the corresponding phenol, which
was achieved in an efficient manner (95% yield) through a two-
step process: (a) palladium mediated coupling of the aryl
chloride with bis(pinacolato)diboron to afford aryl boronic ester
2017 and (b) oxone oxidation of the boronic ester to phenol 21.18
The Boc group was removed with HCl to give the amine salt
22 that was ready for coupling with acid 23. Acid 23 was
prepared from 2-hydroxy-5-methylpyridine through coupling
with ethyl 2-bromoisobutyrate and subsequent hydrolysis. The
amide formation between amine 22 and acid 23 was performed
at 50 °C with EDC as the coupling reagent that afforded 24 in
85% yield.19 Finally, phenol 24 was reacted with in situ
generated 18FCH2CH2Br,20 completing the synthesis of PET
tracer [18F]-16.11a
(7) Reviews: (a) Gifford, A. N.; Makriyannis, A.; Volkow, N. D.; Gatley,
S. J. In vivo imaging of the brain cannabinoid receptor. Chem. Phys.
Lipids 2002, 121, 65-72. (b) Lindsey, K. P.; Glaser, S. T.; Gatley,
S. J. Imaging of the Brain Cannabinoid System. In Handbook of
Experimental Pharmacology; Pertwee, R. G., Ed.; Springer: Berlin,
2005; Vol. 168, pp 425-443. For two recent examples of alkylindole-
like radioligands, see: (c) Willis, P. G.; Pavlova, O. A.; Chefer, S.
I.; Vaupel, D. B.; Mukhin, A. G.; Horti, A. G. Synthesis and
structure-activity relationship of a novel series of aminoalkylindoles
with potential for imaging the neuronal cannabinoid receptor by
positron emission tomography. J. Med. Chem. 2005, 48, 5813-5822.
(d) Deng, H.; Gifford, A. N.; Zvonok, A. M.; Cui, G.; Li, X.; Fan,
P.; Deschamps, J. R.; Flippen-Anderson, A. L.; Gatley, S. J.;
Makriyannis, A. Potent cannabinergic indole analogues as radioio-
dinatable brain imaging agents for the CB1 cannabinoid receptor. J.
Med. Chem. 2005, 48, 6386-6392.
(8) Willis, P. G.; Katoch-Rouse, R.; Horti, A. G. Regioselective F-18
radiolabeling of AM694, a CB1 cannabinoid receptor ligand. J.
Labelled Compd. Radiopharm. 2003, 46, 799-804.
(9) (a) Gatley, S. J.; Lan, R.; Volkow, N. D.; Pappas, N.; King, P.; Wong,
C. T.; Gifford, A. N.; Pyatt, B.; Dewey, S. L.; Makriyannis, A.
Imaging the brain marijuana receptor: development of a radioligand
that binds to cannabinoid CB1R in vivo. J. Neurochem. 1998, 70,
417-423. For clinical studies with [123I]AM281, see: (b) Berding,
G.; Muller-Vah, K.; Schneider, U.; Gielow, P.; Fitschen, J.; Stuhr-
mann, M.; Harke, H.; Buchert, R.; Donnerstag, F.; Hofmann, M.;
Knoop, B. O.; Brooks, D. J.; Emrich, H. M.; Knapp, W. H. [123I]-
AM281 single-photon emission computed tomography imaging of
central cannabinoid CB1 receptors before and after ∆9-tetrahydro-
[18F]-16 was evaluated in propofol-anesthetized rhesus mon-
keys as a potential PET ligand.11b Baseline scans after a single
iv (5 mCi) administration revealed that [18F]-16 rapidly pen-
etrated the blood-brain barrier and accumulated in most gray
matter regions (CB1R-rich area; see Figure 3), reaching a
maximum signal in ∼2 h. A blockade experiment was also

3430 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 15
Letters
cannabinol therapy and whole-body scanning for assessment of
radiation dose in Tourette patients. Biol. Psychiatry 2004, 55, 904-
915. For clinical studies with [124I]AM281, see: (c) Berding, G.;
Schneider, U.; Gielow, P.; Buchert, R.; Donnerstag, G.; Brandau,
W.; Knapp, W. H.; Emrich, H. M.; Muller-Vahl, K. Feasibility of
central cannabinoid CB1 receptor imaging with [124I]AM281 PET
demonstrated in a schizophrenic patient. Psychiatry Res. Neuroim-
aging 2006, 147, 249-256.
(13) Felder, C. C.; Joyce, K. E.; Briley, E. M.; Mansouri, J.; Mackie, K.;
Blond, O.; Lai, Y.; Ma, A. L.; Mitchell, R. L. Comparison of the
pharmacology and signal transduction of the human cannabinoid CB1
and CB2 receptors. Mol. Pharmacol. 1995, 48, 443-450.
(14) The synthesis of 2 was achieved following the general scheme
outlined in ref 10, and the detailed procedure was given in the
Supporting Information. This also applies to other compounds such
as 3-9 and the compounds in Table 1.
(10) (a) Fan, H.; Revert, H. T.; Holt, D. P.; Dannals, R. F.; Horti, A. G.
Synthesis of 1-(2,4-dichlorophenyl)-4-cyano-5-(4-[11C]methoxyphe-
nyl)-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide ([11C]JHU75528)
and 1-(2-bromophenyl)-4-cyano-5-(4-[11C]methoxyphenyl)-N-(pip-
eridin-1-yl)-1H-pyrazole-3-carboxamide ([11C]JHU75575) as potential
radioligands for PET imaging of cerebral cannabinoid receptor. J.
Labelled Compd. Radiopharm. 2006, 49, 1021-1036. (b) Horti, A.
G.; Fan, H.; Kuwabara, H.; Hilton, J.; Ravert, H. T.; Holt, D. P.;
Alexander, M.; Kumar, A.; Rahmim, A.; Scheffel, U.; Wong, D. F.;
Dannals, R. F. [11C]-JHU75528: a radiotracer for PET imaging of
CB1 cannabinoid receptors. J. Nucl. Med. 2006, 47, 1689-1696.
(11) This paper emphasizes the medicinal chemistry efforts that led to
the discovery of the described CB1R PET tracer ([18F]-16). For its
synthesis from the phenol precursor, see: (a) Hamill, T. G.; Lin, L.
S.; Liu, P.; Jewell, J. P.; Goulet, M. T.; Hagmann, W. K.; Fong, T.
M.; Hargreaves, R. J.; Burns, H. D. Synthesis of cannabinoid CB1
receptor PET tracers labelled with carbon-11 and fluorine-18 ([18F]-
MK-9470). J Labelled Compd. Radiopharm., in press. For detailed
in vivo PET imaging studies of this PET tracer, see: (b) Burns, H.
D.; Van Laere, K.; Sanabria-Bohorquez, S.; Hamill, T. G.; Bormans,
G.; Eng, W.; Gibson, R. E.; Ryan, C.; Connolly, B. M.; Patel, S.;
Krause S. M.; Van Hecken, A.; Dupont, P.; Hagmann, W. K.; Jewell,
J. P.; Lin, L. S.; Liu, P.; Goulet, M. T.; De Lepeleire, I.; Cote, J.;
Gottesdiener, K.; Wagner, J. A.; Rothenberger, P.; de Hoon, J.;
(15) Hamill, T. G.; Krause, S.; Ryan, C.; Bonnefous, C.; Govek, S.;
Seiders, T. J.; Cosford, N. D. P.; Roppe, J.; Kamenecka, T.; Patel,
S.; Gibson, R. E.; Sanabria, S.; Riffel, K.; Eng, W.; King, C.; Yang,
X.; Green, M. D.; O’Malley, S. S.; Hargreaves, R.; Burns, H. D.
Synthesis, characterization, and first successful monkey imaging
studies of Metabotropic glutamate receptor subtype 5 (mGluR5) PET
radiotracers. Synapse 2005, 56, 205-216.
(16) For experimental details, see Supporting Information.
(17) Ishiyama, T.; Ishida, K.; Miyaura, N. Synthesis of pinacol arylbor-
onates via cross-coupling reaction of bis(pinacolato)diboron with
chloroarenes catalyzed by palladium(0)-tricyclohexylphosphine com-
plexes. Tetrahedron 2001, 57, 9813-9816.
(18) Webb, K. S.; Levy, D. A facile oxidation of boronic acids and boronic
esters. Tetrahedron Lett. 1995, 36, 5117-5118.
(19) HPLC analysis revealed that the phenol ester was formed as an
intermediate that slowly converted to the thermodynamically more
stable amide product at 25 °C. At 50 °C, the kinetic ester product
was rapidly converted to the desired amide product 24.
(20) Zhang, M.-R.; Furutsuka, K.; Maeda, J.; Kikuchi, T.; Kida, T.;
Okauchi, T.; Irie, T.; Suzuki, K. N-[18F]fluoroethyl-4-piperidyl acetate
([18F]FEtP4A): a PET tracer for imaging brain acetylcholinesterase
in vivo. Bioorg. Med. Chem. 2003, 11, 2519-2527.
Mortelmans, L.; Fong, T. M.; Hargreaves, R. [18F]MK-9470:
a
position-emission tomography (PET) tracer for in vivo human PET
brain imaging of the cannabinoid 1 receptor. Proc. Natl. Acad. Sci.
U.S.A. 2007, 104, 9800-9805.
(21) Chen, C.; Frey, L.; Shultz, S.; Wallace, D. J.; Marcantonio, K.;
Payack, J. F.; Vazuez, E.; Springfield, S. A.; Zhou, G.; Liu, P.;
Kieczykowski, G. R.; Chen, A. M.; Phenix, B.; Singh, U.; Strine, J.;
Izzo, B.; Krska, S. Catalytic, enantioselective synthesis of a novel,
acyclic cannabinoid-1 receptor inverse agonist for the treatment of
obesity. Org. Proc. Res. DeV. 2007, 11, 616-623.
(12) Lin, L. S.; Lanza, T. J., Jr.; Jewell, J. P.; Liu, P.; Shah, S. K.; Qi, H.;
Tong, X.; Wang, J.; Xu, S.; Fong, T. M.; Shen, C.-P.; Lao, J.; Chen,
J.; Shearman, L. P.; Stribling, D. S.; Rosko, K.; Strack, A.; Marsh,
D. J.; Feng, Y.; Kumar, S.; Samuel, K.; Yin, W.; Van der Ploeg, L.;
Goulet, M. T.; Hagmann, W. K. Discovery of N-[(1S,2S)-3-(4-
Chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-{[5-
(trifluoromethyl)pyridin-2-yl]oxy}propanamide (MK-0364), a novel,
acyclic cannabinoid-1 receptor inverse agonist for the treatment of
obesity. J. Med. Chem. 2006, 49, 7584-7587.
(22) A new CB1R PET tracer from NIH/Lilly/Karolinska ([11C]MePPEP)
became known on the NIH Web site (http://clinicalstudies.info.nih.
gov/detail/A_2007-M-0118.html) after this manuscript was submitted.
JM070131B