Discovery of Phosphodiesterase 10A (PDE10A) PET Tracer AMG 580 to Support Clinical Studies

Article abstract of DOI:10.1021/acsmedchemlett.6b00185

We report the discovery of PDE10A PET tracer AMG 580 developed to support proof of concept studies with PDE10A inhibitors in the clinic. To find a tracer with higher binding potential (BP_ND) in NHP than our previously reported tracer 1, we implemented a surface plasmon resonance assay to measure the binding off-rate to identify candidates with slower washout rate in vivo. Five candidates (2-6) from two structurally distinct scaffolds were identified that possessed both the in vitro characteristics that would favor central penetration and the structural features necessary for PET isotope radiolabeling. Two cinnolines (2, 3) and one keto-benzimidazole (5) exhibited PDE10A target specificity and brain uptake comparable to or better than 1 in the in vivo LC-MS/MS kinetics distribution study in SD rats. In NHP PET imaging study, [¹⁸F]-5 produced a significantly improved BP_ND of 3.1 and was nominated as PDE10A PET tracer clinical candidate for further studies.

Full text of DOI:10.1021/acsmedchemlett.6b00185

Letter
pubs.acs.org/acsmedchemlett
Discovery of Phosphodiesterase 10A (PDE10A) PET Tracer AMG 580
to Support Clinical Studies
Essa Hu,*,† Ning Chen,† Roxanne K. Kunz,† Dah-Ren Hwang,Δ Klaus Michelsen,⊥ Carl Davis,‡ Ji Ma,
Jianxia Shi, Dianna Lester-Zeiner,∥ Randall Hungate,† James Treanor,§ Hang Chen,∥
and Jennifer R. Allen†
‡
§
†Department of Medicinal Chemistry, Department of Pharmacokinetics and Drug Metabolism, Department of Neuroscience, and
ΔDepartment of Early Development, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 93012-1799, United States
∥Department of Neuroscience and Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., 1120 Veterans Boulevard,
South San Francisco, California 94080, United States
⊥Department of Molecular Structure and Characterization, Amgen Inc., 360 Binney Street, Cambridge, Massachusetts 02142, United
States
S
* Supporting Information
ABSTRACT: We report the discovery of PDE10A PET tracer AMG 580 developed to support
proof of concept studies with PDE10A inhibitors in the clinic. To find a tracer with higher binding
potential (BPND) in NHP than our previously reported tracer 1, we implemented a surface
plasmon resonance assay to measure the binding off-rate to identify candidates with slower
washout rate in vivo. Five candidates (2−6) from two structurally distinct scaffolds were identified
that possessed both the in vitro characteristics that would favor central penetration and the
structural features necessary for PET isotope radiolabeling. Two cinnolines (2, 3) and one keto-
benzimidazole (5) exhibited PDE10A target specificity and brain uptake comparable to or better
than 1 in the in vivo LC−MS/MS kinetics distribution study in SD rats. In NHP PET imaging
study, [18F]-5 produced a significantly improved BPND of 3.1 and was nominated as PDE10A PET
tracer clinical candidate for further studies.
KEYWORDS: Phosphodiesterase, tracer, receptor occupancy, positron emission tomography, radiotracer, brain penetration
ositron emission tomography (PET) imaging using a
radiolabeled tracer is a direct and noninvasive technology
PDE10A, in particular, is reported to be most highly expressed
in the striatum medium spiny neuron (MSN), a region of the
brain that has been associated with the pathophysiology of
schizophrenia. Reports of the high density and localization of
PDE10A in the brain suggested likelihood of a strong and
specific PET signal essential for imaging and TO calculations.
Functionally, phosphodiesterases hydrolyze the 3′-5′ phospho-
diester bonds on secondary messengers cyclic adenosine
monophosphate (cAMP) and cyclic guanidine monophosphate
(cGMP) to convert them into adenosine monophosphate
(AMP) and guanidine monophosphate (GMP). Microdialysis
and microwave methods have been reported for measuring the
changes of cAMP/cGMP levels in vivo as a means to assess the
efficacy of drug candidates in preclinical species. However,
these methodologies would not be translatable to the clinic.
Having a selective PDE10A tracer would not only demonstrate
target engagement by CNS TO but also enable translation of
preclinical to clinical findings. The value of having PDE10A
P
platform that has found broad utility in the clinic. Some well-
known examples include: 2-[18F]-fluoro-2-deoxy-D-glucose
(FDG) used to measure tumor metabolism to monitor cancer
progression, [11C]-2-(4-(methylamino)phenyl)-6-hydroxyben-
zothiazol (PIB) and [18F]-florbetaben designed to assess β-
amyloid plaque accumulation in the brain to diagnose
Alzheimer’s disease, and [11C]-raclopride and [18F]-fallypride
designed to quantify target occupancy (TO) at dopamine
receptors to enable correlation of TO with clinical end points
or adverse events. For novel therapeutic agents targeting the
central nervous system (CNS), PET imaging provides an
assessment of CNS target engagement more directly than other
readouts such as biomarker levels in the plasma or the cerebral
spinal fluid (CSF). Nevertheless, it is still uncommon for
research groups to develop both a novel, therapeutic agent and
a novel, target specific PET tracer in parallel due to cost, time,
and resource limitations.1
When we initiated a drug discovery effort to develop a
phosphodiesterase 10A (PDE10A) inhibitor, it quickly became
apparent that the profile of this CNS target was particularly
suitable for tracer development. PDE10A belongs to a family of
11 isoforms found to be highly compartmentalized in the body.
Received: May 3, 2016
Accepted: May 19, 2016
© XXXX American Chemical Society
A
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PET tracers in the clinic has been echoed in the research
community as reflected by recent tracer publications.1
reduce the wash out rate observed in the NHP PET study.
Thus, a surface plasmon resonance (SPR) binding assay was
incorporated into the flow scheme to assess the binding
kinetics. Based on the formula {T1/2 = Ln(2)/kd}, compounds
Once we decided to develop a PDE10A radiotracer, we
explored various approaches to expedite the tracer discovery
process in hopes of reducing resource burden. Recently, we
reported the rapid identification of PDE10A tracer 5-(6,7-
dimethoxycinnolin-4-yl)-N-isopropyl-3-methylpyridin-2-amine
(AMG 7980, 1) using a combination of preselected in vitro
characteristics to favor central uptake and liquid chromatog-
raphy-tandem mass spectrometry (LC−MS/MS) technology to
quantify compound exposures down to microgram levels in
brain tissues (Figure 1).2 The utility of tracer 1 was
with binding half-life, T1/2, at least 5-fold longer than 1 (T1/2
=
0.04 min) were advanced into the in vivo LC−MS/MS kinetics
study. Binding specificity was quantified as a ratio of a
compound’s area under the curve (AUC) in the target region
(striatum; Str) over the control region (thalamus; Tha). Brain
uptake was calculated as the percentage of injected dose
measured in the target region per gram of tissue (%ID/g). Five
structurally distinct and novel analogues emerged as a result of
the LC−MS/MS study (Figure 2). In this report, we describe
Figure 1. PDE10A tracer 1.
demonstrated in an in vivo rodent TO study with a structurally
distinct PDE10A inhibitor. With a capacity of four compounds
every 2 weeks, this LC−MS/MS TO measurement platform
using tracer 1 provided the critical path study for in vivo
evaluation of our own PDE10A candidates in-house.3−5
Unfortunately, our hope to advance 1 as a PDE10A PET
tracer could not be realized as [11C]-1 exhibited suboptimal
binding potential with respect to the nondisplaceable tracer
concentration (BPND) of 0.62 by simplified reference tissue
model (SRTM) and 0.9 by one tissue compartment model
(1TC) in a nonhuman primate (NHP) PET imaging study.6
Since a radiotracer’s BPND value is proportional to the level of
precision of its TO measurements, we decided 1 would not be
sufficient to support our clinical studies. Analysis of the PET
imaging data revealed excellent brain uptake of [11C]-1 but also
a fast wash out rate. We hypothesized that increasing the tracer
target retention time would address the issue. Thus, a renewed
effort was initiated to find a PET tracer candidate with
improved BPND. This report describes the initial hypothesis,
strategy, screening, selection, and design that led to the
identification of PET tracer clinical candidate AMG 580.
Additional profiling of the candidate both in vitro and in vivo,
across various species and in PET imaging studies, have been
reported in separate communications.7,8
This time, we expanded the scope of structural diversity to
include multiple scaffolds investigated by our in-house PDE10A
inhibitor discovery efforts (see Supporting Information for flow
scheme).3−5,9−11 Historical compounds were filtered based on
a specific set of in vitro parameters that favor brain penetration:
(1) PDE10A binding affinity comparable to or better than 1
(PDE10A IC50 = 1.9 nM), (2) PDE selectivity greater than
100-fold against the rest of the PDE isoforms (1−9, 11), (3)
permeable, and (4) low P-gp efflux ratio. Candidates must also
possessed the molecular structures amenable to radiolabeling
with PET isotopes [11C] or [18F].12−14 New analogues were
designed based on our reported cocrystal structures, which
revealed a potential benefit from exploiting the solvent exposed
regions of the PDE10A binding domain. We hypothesized that
decreasing the binding off rate of the tracer candidates could
Figure 2. Structures of five distinct PDE10A inhibitors 2−6 as tracer
candidates.
these five lead candidates, their in vitro and in vivo profiles, and
the identification of one suitable PDE10A PET tracer as a
clinical candidate. Synthetic routes used to make tracer
candidates 2−6 are described in the Supporting Information
section.
In the in vivo LC−MS/MS kinetics study, all five candidates
exhibited good levels of specificity for PDE10A enriched
striatum over thalamus (AUCStr/Tha > 5) and good brain uptake
(%ID/g > 0.5) (Table 1 and Figure 3).15 In the PDE10A
biochemical assay, the new analogues exhibited IC50 values
ranging from 1.7 nM (activities comparable to 1) to 0.1 nM
(nearly 20-fold more potent than 1). The magnitude of increase
in the biochemical activity did not always correlate with
improvement in the binding T1/2. Cinnoline 2 exhibited
PDE10A activity similar to tracer 1, and yet, its binding off-
rate was 6-fold slower compared to 1. Although cinnoline 3 was
7-fold more potent than keto-benzimidazole 4 in the PDE10A
assay, its binding T1/2 was only 21-fold longer compared to the
32-fold binding T1/2 improvement observed with 4. The most
dramatic difference was found with keto-benzimidazole 6, with
a PDE10A IC50 of 0.3 nM and an 85-fold increase in binding
T
1/2. Not surprisingly, improvements in binding off-rate were
not reflected in the striatum to thalamus ratio as these
measurements were taken at a single time point of 10 min after
compound dosing. Nevertheless, the striatum to thalamus ratio
was one preliminary indicator of the signal-to-noise ratio in the
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LC−MS/MS TO study in SD rats using our recently reported
PDE10A clinical candidate, AMG 579,17 as the blocker. Blocker
was administered orally at doses 0.1, 0.3, 1, 3, 10, and 30 mg/
kg, 1.5 h before administration of tracer 5 (5 μg/kg i.v.).
Tissues from the striatum and the thalamus, as well as blood
samples, were collected after 30 min. Both tracer and blocker
levels in the brain tissues were determined by LC−MS/MS. As
shown in Figure 4, tracer 5 was able to measure TO with our
Table 1. Profile of Five Lead Candidates 2−6 That Exhibited
Improved Binding T1/2, Good Specificity in PDE10A
Enriched Region in CNS, and Good Brain Uptake
b
LC−MS/MS TO
PDE10A IC50
(nM)
binding T
a1/2
c
d
compd
(fold)
[AUCStr/Tha
]
[%ID/g]
1
2
3
4
5
6
1.9
1.7
0.1
0.7
0.1
0.3
1×
6×
21×
32×
16×/61×
85×
9.4
12.6
8.7
1.2
0.8
0.8
0.3
1.2
1.0
5.6
e
23
5.7
a
Fold over 1. Binding T1/2 values were calculated based on measured
b
Kd using the formula: {T1/2 = Ln(2)/kd}. LC−MS/MS study was
conducted in Sprague−Dawley (SD) rats at n = 10 per group. The
c
compounds were dosed i.v. and formulated in 100% DMSO. Ratio of
AUC of compound in striatum (Str) over AUC of compound in
d
thalamus (Tha) at t = 10 min after dosing. Percentage of injected
dose (ID) of compound in the striatum per gram of tissue sampled.
e
See Supporting Information section for additional experimental data
on 5.
Figure 4. Tracer blocking study using 5 as tracer and PDE10A
inhibitor AMG 579 as blocker. Blocker was dosed orally at doses 0.1,
0.3, 1, 3, 10, and 30 mg/kg. Tracer 5 was dosed i.v. at 5 μg/kg 1.5 h
post blocker dosing. Tissues were collected and analyzed 30 min post-
tracer dosing. N = 3−4 animals per group.
in vivo PET imaging study. Thus, with tracer 1 as the
benchmark, we advanced only compounds 2, 3, and 5,16 which
produced striatum to thalamus ratio comparable or superior to
1.
Prior to in vivo NHP PET imaging study, all three lead
candidates were further profiled in rats to make sure the tracer
signals were saturable and that the tracer candidates could be
blocked by a PDE10A inhibitor. The LC−MS/MS methods
utilized were previously described in our report on tracer 1.2 As
an example, we reported that candidate 5 produced a saturable,
specific, in vivo binding kinetics profile in the LC−MS/MS
study.7 To demonstrate that the tracer can be blocked and thus
can be used to measure TO in vivo, we performed an in vivo
blocker in a dose-dependent manner, reaching 63% PDE10A
occupancy at 30 mg/kg dose. This study confirmed the utility
of tracer candidate 5 for in vivo measurement of PDE10A
inhibitor TO.7
Both cinnoline candidates 2 and 3 were eliminated as a result
of the PET imaging study. [11C]-2 exhibited fast washout
presumably because the 6-fold improvement in binding T1/2
over 1 was not sufficient to have a significant impact on its in
vivo off rate. Meanwhile, [11C]-3 formed a significant amount
Figure 3. In vivo kinetics distribution of tracer candidates 2−6 in SD rats. Compounds 2−5 were dosed i.v. at 10 μg/kg, while 6 was dosed at 5 μg/
kg. The concentration of tracer candidates in the striatum (STR, blue dot), thalamus (THA, purple dot), and plasma (PLA, red dot) were measured
by LC−MS/MS. Specific uptake was calculated by subtraction of compound level in the thalamus from compound level in the striatum (STR-THA,
green dot). Error bars represent standard error of mean, and n = 3−4 animals per group. In vivo kinetics distribution graphs for tracer candidates (A)
2, (B) 3, (C) 4, (D) 5, and (E) 6.
C
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ACS Medicinal Chemistry Letters
Letter
[18F]-5, experimental methods, and additional references
(PDF)
of brain-penetrant radioactive metabolites in NHP suggesting
the molecule was metabolized differently in NHP compared to
cinnoline 1, which was absent of brain penetrant radioactive
metabolites. Gratifyingly, [18F]-5 produced promising results.
In the NHP PET imaging study, [18F]-5 exhibited BPND of 3.1
in the PDE10A rich striatum region by SRTM, which
constitutes a significant improvement compared to BPND of
0.6 for [11C]-1. High levels of specific tracer uptake were
observed in the PDE10A enriched striatum. Additional details
of the NHP PET imaging study along with tissue distribution of
[18F]-5 have been reported in separate communications.8
While developing radiochemistry conditions to make [18F]-5
from precursor 10,18 we discovered our reaction conditions
caused racemization of the stereocenter. This finding made
advancement of [18F]-5 as a single enantiomer technically
challenging. Limited resources precluded us from finding a new
radiolabeling condition. Addition of a chiral HPLC separation
step after radiosynthesis would lengthen the PET tracer
production time and significantly reduce the overall radio-
chemical yield. Since both enantiomers of 5 exhibited the
desired kinetics profiles when profiled as cold compounds by
LC−MS/MS (see Supporting Information), we assessed the
option of advancing [18F]-5 as a racemate by putting the
compound in a battery of profiling studies and in vivo target
occupancy studies in both rats and NHP.7,8 The data showed 5
was well behaved in vivo and could be modeled well. Thus, we
advanced [18F]-5 as our clinical PET tracer candidate.
Having a PET imaging tracer to support clinical proof of
concept studies is a valuable asset to any CNS drug
development program. This noninvasive technology provides
a direct means to demonstrate target engagement in the brain
in clinical trials and facilitates translation of preclinical findings.
Our first PDE10A tracer (1) exhibited fast washout in vivo
resulting in BPND < 1 in the NHP PET imaging study. Since
BPND is a critical parameter that impacts both the confidence
and the resolution of the PET TO measurement we set out to
identify a better PDE10A PET imaging tracer. Historical
analogues from several structurally distinct scaffolds in-house
were filtered, and novel compounds were designed to find
candidates that would meet our preselected in vitro criteria. To
identify candidates with slower off rates than 1, binding T1/2
was assessed by an SPR spectroscopy binding assay. Three of
the five compounds profiled in the in vivo LC−MS/MS kinetics
study achieved in vivo target specificity (AUCStr/Tha) and brain
uptake (%ID/g) comparable or better than 1. All three
candidates (2, 3, and 5) exhibited saturable and specific binding
in SD rats in vivo and enabled the measurement of PDE10A
inhibitor TO in vivo. When advanced into the in vivo NHP
PET imaging study, [18F]-5 emerged as the superior tracer
candidate exhibiting the desired slower washout rate, minimal
radioactive metabolite uptake in the brain, and high BPND of 3.1
in the striatum. With our goal of finding a PDE10A PET tracer
with better BPND than 1 achieved, [18F]-5 was advanced into
clinical studies as AMG 580.
AUTHOR INFORMATION
Corresponding Author
*Phone: 805-313-5300. E-mail: ehu@amgen.com.
■
Notes
The authors declare no competing financial interest.
ABBREVIATIONS
■
1TC, one tissue compartment model; BPND, binding potential
nondisplaceable; CNS, central nervous system; DAST,
diethylaminosulfur trifluoride; DCM, dichloromethane; DME,
dimethoxyethane; EtOAc, ethyl acetate; LC−MS/MS, liquid
chromatography−tandem mass spectrometry; NHP, nonhu-
man primates; PDE, phosphodiesterase; PET, positron
emission tomography; SEM, standard error of the mean;
SPR, surface plasmon resonance; SRTM, simplified reference
tissue model; THF, tetrahydrofuran; TO, target occupancy
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ASSOCIATED CONTENT
■
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* Supporting Information
The Supporting Information is available free of charge on the
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