Synthesis and evaluation of 5-fluoro-2-aryloxazolo[5,4- b ]pyridines as β-amyloid PET ligands and identification of MK-3328

Article abstract of DOI:10.1021/ml200018n

5-Fluoro-2-aryloxazolo[5,4-b]pyridines were synthesized and investigated as potential ¹⁸F containing β-amyloid PET ligands. In competition binding assays using human AD brain homogenates, compounds 14b, 16b, and 17b were identified as having favorable potency versus human β-amyloid plaque and were radiolabeled for further evaluation in in vitro binding and in vivo PET imaging experiments. These studies led to the identification of 17b (MK-3328) as a candidate PET ligand for the clinical assessment of β-amyloid plaque load.

Full text of DOI:10.1021/ml200018n

LETTER
pubs.acs.org/acsmedchemlett
Synthesis and Evaluation of 5-Fluoro-2-aryloxazolo[5,4-b]pyridines as
β-Amyloid PET Ligands and Identification of MK-3328
Scott T. Harrison,*,† James Mulhearn,† Scott E. Wolkenberg,† Patricia J. Miller,‡ Stacey S. O’Malley,‡
Zhizhen Zeng,‡ David L. Williams, Jr.,‡ Eric D. Hostetler,‡ Sandra Sanabria-Bohꢀorquez,‡ Linda Gammage,‡
Hong Fan,‡ Cyrille Sur,‡ J. Christopher Culberson,§ Richard J. Hargreaves,‡ Jacquelynn J. Cook,‡
George D. Hartman,† and James C. Barrow†
†Departments of Medicinal Chemistry, ‡Imaging, and §Chemical Modeling and Informatics, Merck Research Laboratories,
Merck & Co., Inc., P.O. Box 4, West Point, Pennsylvania 19486, United States
S Supporting Information
b
ABSTRACT: 5-Fluoro-2-aryloxazolo[5,4-b]pyridines were synthesized and investigated as
potential 18F containing β-amyloid PET ligands. In competition binding assays using human
AD brain homogenates, compounds 14b, 16b, and 17b were identified as having favorable
potency versus human β-amyloid plaque and were radiolabeled for further evaluation in in vitro
binding and in vivo PET imaging experiments. These studies led to the identification of 17b (MK-
3328) as a candidate PET ligand for the clinical assessment of β-amyloid plaque load.
KEYWORDS: Alzheimer’s disease, β-amyloid plaque, fluorine-18, positron emission tomogra-
phy, PET, oxazolo[5,4-b]pyridine
lzheimer’s disease (AD) is a progressive neurodegenerative
disorder which was estimated to afflict 26.6 million people
A
worldwide as of 2006,1 with many more being affected as
caregivers of those with this debilitating disease. Although
marketed treatments for AD temporarily improve cognitive
symptoms in patients, they fail to significantly slow disease
progression. Several novel therapeutics are under development
which have the potential to intervene in the underlying mechan-
isms of AD, and biomarkers for detecting affected patient
populations and for measuring response to these therapies are
needed.2 Many in the Alzheimer’s research community believe
that successful alteration of the disease’s trajectory may require
therapeutic intervention at the mild cognitive impairment (MCI)
symptomatic stage, before the onset of potentially irreversible
neurodegeneration.3 Whereas clinical diagnosis of AD via tests
of cognition is sufficient at late stages, early diagnosis of
prodromal or predementia AD is less straightforward and
requires evidence of both episodic memory loss and biomarker
changes supportive of pathological processes.4
Several noteworthy efforts are underway to identify early
clinical markers of AD.5 While promising, most predictive
markers are indirect measures of underlying disease pathology
or are medically invasive. A more direct and noninvasive
approach, in particular, the assessment of β-amyloid (Aβ) plaque
deposits in the brain via positron emission tomography (PET)
imaging, has demonstrated success in clinical settings. To date,
several Aβ-binding PET ligands have effectively differentiated
AD from non-AD patients. [11C]PIB (1, Figure 1)6,7 is the most
thoroughly studied amyloid PET ligand and recently has been
correlated with other clinical AD biomarkers.8 Although not as
well characterized as PIB, Astra-Zeneca’s [11C]AZD2184 (2)
shows promise as a human amyloid imaging agent, as it has
Figure 1. Structures of selected amyloid PET ligands and our reference
radioligand 8, [3H3]DMAB.
demonstrated lower levels of nonspecific binding than PIB in
preclinical studies.9ꢀ11
While these tracers are effective, the short half-life of 11C (∼20
min) limits the use of [11C]PIB and [11C]AZD2184 to PET
imaging centers with cyclotrons in their immediate vicinity.
Received: January 24, 2011
Accepted: March 15, 2011
Published: April 18, 2011
r
2011 American Chemical Society
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Scheme 1a
Table 1. Affinity of 5-Fluoro-2-aryloxazolo[5,4-b]pyridines
for Human β-Amyloid Plaque Deposits
a Reagents and conditions: (a) 9, (CH3)2CdC(N(CH3)2)Cl, CH2Cl2,
25 °C. (b) 10a or 10b, pyridine, 25 °C. (c) K2CO3 or Cs2CO3, DMF,
microwave, 165 °C; optionally TFA, 25 °C. (d) K18F, kryptofix 2.2.2,
DMSO, microwave, 140 °C, 3 min. TFA = trifluoroacetic acid.
Because 18F has a much longer half-life (110 min), 18F-based
tracers may be used at PET imaging sites much further away from
radionuclide production sites, enabling increased access for
patients. Several research programs have engaged in the design
and discovery of 18F amyloid PET ligands, culminating in the
discovery of [18F]FDDNP12 (3), GE-067 (Flutemetamol, 4),13
[18F]AV-1 (Florbetaben, 5),14,15 [18F]AV-45 (Florbetapir,
6),16,17 and AZD4694 (7).18
Based on the preclinical and clinical data available,12ꢀ18 we
estimated that a successful amyloid imaging agent must have high
affinity for β-amyloid plaque (Kd < 20 nM) with minimal
nonspecific binding in order to provide a large specific signal
for plaque detection. Also important is the behavior of the tracer
in in vivo imaging studies in animals lacking plaque, where the
tracer should exhibit high brain uptake and rapid washout
kinetics. Published data on amyloid ligand candidates reveals
that highly lipophilic tracers often exhibit elevated retention in
white matter which, in imaging studies, can affect the signal-to-
noise ratio and interfere with the differentiation of AD and non-
AD patients.15 Decreasing lipophilicity (e.g., cLogP) is one
method that may be employed to reduce nonspecific binding
to brain tissue.19 Pairwise comparisons of closely related amyloid
binders suggests that this approach is valid, as observed in the
improved nonspecific binding profile of AZD2184 (cLogP20
=
a Values are means of at least two experiments. b Calculated using
AlogP98.20
2.84) versus PIB (cLogP = 3.45) as well as AV-45 (cLogP = 3.13)
versus AV-1 (cLogP = 3.75).
Herein we report our efforts in this area, involving the
synthesis and evaluation of oxazolo[5,4-b]pyridines that can be
labeled with 18F as potential imaging agents for β-amyloid
plaque. To characterize binding of newly synthesized com-
pounds, a competition binding assay in human AD cortex
homogenates was employed using [3H3]DMAB (8) as a refer-
ence radioligand. This compound was identified via radiolabeling
of selected structures from the Merck compound collection with
high structural similarity to literature amyloid plaque ligands.
[3H3]DMAB (8) has a Kd of 25 nM in human AD brain
homogenates with low levels of nonspecific binding, making it
a suitable reference radioligand for competition binding assays.
From a design perspective, 8 also served as a lead structure in the
design of the 5-fluoro-oxazolo[5,4-b]pyridines presented in this
work. Potent compounds possessing low calculated logP and
lacking P-glycoprotein (P-gp) susceptibility were radiolabeled
with tritium for examination in more detailed in vitro binding
assays and with 18F for evaluation in rhesus monkey PET studies.
Because [11C]PIB does not bind with high affinity to plaque in
rhesus monkey brain,21 we did not use animal models of AD in
in vivo imaging experiments to predict the behavior of tracer
candidates in patients.
Unlabeled oxazolo[5,4-b]pyridine analogs were synthesized
starting from 3-amino-2,6-difluoropyridine 10a22 (Scheme 1)
and a variety of commercially available and prepared carboxylic
acids 9. Activation of the carboxylic acids 9 with Ghosez’
reagent,23 followed by reaction with 10a in the presence of
excess pyridine afforded amides of type 11a. Focused libraries
were prepared by parallel concentration of the crude reaction
mixtures and direct passage into the next step; however, conver-
sions were generally higher if the amides were first isolated and
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Table 2. Binding Affinity of Tritium-Labeled 14b, 16b, and
17b versus Human AD Brain Homogenates from Three
Different Donors
compd
Kd (nM)a
Bmax (nM)
Bmax/Kd
NDBb
[3H3]14b
[3H3]16b
[3H3]17b
4.5 ( 0.6
6.4 ( 0.9
9.6 ( 0.3
2088 ( 231
1454 ( 140
1100 ( 290
464 ( 80
232 ( 40
117 ( 34
50%
50%
35%
a Values are means of three experiments using AD brain homogenates
from different donors. b Nondisplaceable binding, estimated as the
amount of binding observed at the Kd in the presence of 2 μM unlabeled
compound
purified, using either chromatography or precipitation following
the addition of water. Previously described acidic methods for the
conversion of amides of type 11a into oxazolo[5,4-b]pyridines
were poor yielding;24 however, microwave heating of the amides
11a with K2CO3 or Cs2CO3 in DMF afforded the targeted
oxazolo[5,4-b]pyridines 12a, typically with high conversion. In
instances where the starting carboxylate 9 contained a free NꢀH,
the base mediated cyclizations failed to proceed, necessitating
protection with a Boc or p-methoxybenzyl group, which either
spontaneously deprotected during heating or was subsequently
removed with trifluoroacetic acid. Synthesis of 18F labeled
precursors was accomplished via the same route, substituting
commercially available 3-amino-2,6-dichloropyridine 10b in the
first step, leading to 5-chloro-oxazolo[5,4-b]pyridines of type
12b. Microwave heating with [18F]KF and Kryptofix 2.2.2 in
DMSO then afforded [18F]12a.
Previously reported SAR in the 2-arylbenzazole classes of Aβ
plaque ligands suggested that 4- and 3,4-substitutions on the
2-aryl ring are necessary for high amyloid affinity,25 while 2- and
6-substitutions are deleterious, so our own efforts primarily
focused on the 3- and 4-positions (Table 1). While 4-methox-
yphenyl (13) and 4-methylaminophenyl (14a) analogs demon-
strated moderate potency with moderate to high clogP values,
the dimethylamino analog 14b exhibited potent binding, with
only a slightly higher clogP relative to 14a. Attempts to moderate
lipophilicity by incorporation of a ring nitrogen, as in pyridine
analogs 15a and 15b, resulted in a loss of binding affinity.
Constraining the 4-substituent into a ring led to indole analogs
16a and 16b, which were potent at a cost of slightly elevated
lipophilicity. Whereas aza-substitution of 4-amino phenyl com-
pounds was deleterious for binding potency, 7-aza-substitution
of the indoles 16aꢀb, affording the azaindoles 17a and 17b,
caused only a 2-fold loss in binding potency while lowering clogP
by a full unit. N-Methyl analogs (14bꢀ17b) tended to exhibit
improved binding potency relative to their respective des-methyl
analogs (14aꢀ17a). Many closely related and isomeric forms of
the active indoles (16a,b) and azaindoles (17a,b) were investi-
gated; however, the best of these compounds were 2- to 5-fold
less potent (18ꢀ22) and, in most instances, were completely
inactive (e.g., 23ꢀ24). All of the compounds evaluated for
human P-gp susceptibility in this series were not substrates
(P-gp transport ratio < 3) and exhibited high passive permeability
(Papp > 20 ꢁ 10ꢀ6 cm/s), including the lead compounds 14b,
16b, and 17b.26
Figure 2. (a) Autoradiographic images of AD human cortex after
treatment with 5 nM [3H3]-labeled compound. (b) Autoradiographic
images of AD human cortex after treatment with 5 nM [3H3]-labeled
compound in the presence of 1 μM unlabeled compound (self-block).
iodide. Saturation binding studies were conducted using AD
cortex homogenates, to which all three compounds exhibited
potent and saturable binding (Table 2). While 14b and 16b
exhibited more potent binding and higher Bmax/Kd ratios relative
to 17b, the latter compound exhibited lower levels of nondis-
placable binding in AD brain homogenates, estimated as the
percent of total binding at the Kd in the presence of 2 μM
unlabeled compound. The decreased level of nonspecific binding
associated with 17b is consistent with the hypothesis that
nonspecific binding to brain tissue correlates with lipophilicity.
Autoradiographic imaging experiments with human AD brain
slices were used to further differentiate the tritium-labeled lead
compounds (Figure 2). Whereas [3H3]14b, [3H3]17b, and the
positive control [3H3]PIB ([3H3]1)9 exhibited a punctate bind-
ing pattern, [3H3]16b repeatedly failed to do so, presumably due
to a combination of elevated nonspecific binding and a high
affinity of the compound for laboratory plastics (Figure 2,
column a). Self-block with 1 μM unlabeled parent compound
was used to assess nonspecific binding (Figure 2, column b). In
all instances, punctate binding was not observed in the presence
To fully characterize the binding characteristics of 14b, 16b,
and 17b, their corresponding [3H3]methyl analogs were pre-
pared using sodium hydride mediated deprotonation of 14a, 16a,
and 17a, respectively, followed by reaction with [3H3]methyl
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LETTER
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*Telephone: þ1-215-652-7652. Fax: þ1-215-652-6345. E-mail:
scott_harrison@merck.com.
’ ACKNOWLEDGMENT
We are grateful to Ray McClain, April Cox, Anna Dudkina,
and Semhal Berhane for mass-guided HPLC purification of
library compounds, Joan Murphy and Charles W. Ross, III for
HRMS measurements, Sandor L. Varga for NMR structure
determinations, and Cheng Tang, Scott Pollack, and Ashok
Chaudhary for synthesis of tritium labeled compounds.
Figure 3. (a) Decay corrected timeꢀactivity curves for [18F]17b in
cortex (red circles), cerebellum (blue squares), and white-matter (black
diamonds). (b) MRI coregistered rhesus PET image at 45ꢀ90 min with
[18F]17b. Cerebellum was used as a baseline reference.
of a saturating concentration of unlabeled parent compound;
however, all compounds exhibited some degree of diffuse back-
ground binding. Qualitatively, the specific to nonspecific binding
ratio for [3H3]17b appeared to be better than that of [3H3]14b,
suggesting that 17b may be a better amyloid diagnostic agent
in vivo.
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