Leveraging Open Science Drug Development for PET: Preliminary Neuroimaging of 11C-Labeled ALK2 Inhibitors

Article abstract of DOI:10.1021/acsmedchemlett.1c00127

Mutations in the gene encoding activin receptor-like kinase 2 (ALK2) are implicated in the pathophysiology of a pediatric brainstem cancer, diffuse intrinsic pontine glioma (DIPG). Inhibitors of ALK2 that cross the blood-brain barrier have been proposed a

Full text of DOI:10.1021/acsmedchemlett.1c00127

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Letter
Leveraging Open Science Drug Development for PET: Preliminary
11
Neuroimaging of C‑Labeled ALK2 Inhibitors
Emily Murrell, Junchao Tong, David Smil, Taira Kiyota, Ahmed M. Aman, Methvin B. Isaac,
Iain D. G. Watson,* and Neil Vasdev*
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ABSTRACT: Mutations in the gene encoding activin receptor-like
kinase 2 (ALK2) are implicated in the pathophysiology of a pediatric
brainstem cancer, diffuse intrinsic pontine glioma (DIPG). Inhibitors
of ALK2 that cross the blood−brain barrier have been proposed as a
method of treatment for DIPG. As part of an open science approach to
radiopharmaceutical and drug discovery, we developed 11C-labeled
radiotracers from potent and selective lead ALK2 inhibitors to
investigate their brain permeability through positron emission
tomography (PET) neuroimaging. Four radiotracers were synthesized
by 11C-methylation and assessed by dynamic PET imaging in healthy
Sprague−Dawley rats. One of the compounds, [11C]M4K2127,
showed high initial brain uptake (SUV ∼ 2), including in the region
of interest (pons). This data supports the use of this chemotype as a
brain penetrant ALK2 inhibitor that permeates evenly into the pons
with potential application for the treatment of DIPG.
KEYWORDS: Carbon-11, Positron emission tomography, ALK2, DIPG, Blood-brain barrier
the brain (pons) was unknown. Central nervous system (CNS)
ctivin receptor-like kinase 2 (ALK2) is a kinase receptor
Aencoded by the ACVR1 gene. Mutations in ACVR1 drug discovery can be facilitated with position emission
tomography (PET) imaging by measuring the BBB perme-
ability of isotopically labeled drug candidates. In addition, PET
imaging can be used to visualize distribution of the radiotracer
into specific regions of the brain such as the pons. In addition
to our recent work on ALK2 drug discovery, the goal of the
present study was to apply an open science approach for PET
radiotracer discovery, to label four lead potent and ALK2-
selective inhibitors with carbon-11 (half-life = 20.4 min), and
to assess the BBB permeability of these radiotracers by PET
imaging in rodent models. Assessment of the brain
permeability of these compounds as PET radiotracers
identified a candidate radioligand that can be used for further
drug development of ALK2 inhibitors of this chemotype,
facilitating receptor occupancy, target engagement, and dosing
regimen studies.
causing a gain-of-function in ALK2 signaling have been
reported in approximately 25−30% of children with diffuse
intrinsic pontine glioma (DIPG), a rare pediatric brainstem
cancer with a poor prognosis.1−3 DIPG tumors are aggressive
and arise from the brain’s glial tissue in the lowest stem-like
portion of the brain, the pons. Although the pathology of the
relationship is not yet fully known, ALK2 has emerged as a
potential therapeutic target for the treatment of DIPG. Kinase
inhibitors have notoriously poor selectivity, often showing off-
target affinity to other kinases within a family because of the
high degree of structural homology in ATP binding domains.
In the case of ALK2, off-target binding to the closely related
TGFβ pathway receptor ALK5 is of specific concern due to
potential cardiotoxicity.4 In addition, the discovery of kinase
inhibitors that are sufficiently able to cross the blood−brain
barrier (BBB) has been lacking5 and there is no report of work
aiming to measure the degree of penetration of DIPG-directed
therapeutics into the pons.6−8 We recently reported on
leveraging an open science drug discovery model9 to synthesize
a series of 3,5-diphenylpyridine ALK2-selective inhibitors that
cross the BBB for the treatment of DIPG.10,11 The lead
compounds from this effort show brain penetration in rodent
models with total brain to plasma (B/P) ratios of 0.8−1.4,
although distribution into the therapeutic region of interest in
Four lead compounds with IC50 values for ALK2 between
9−19 nM were selected for radiolabeling: M4K2163,
Received: March 2, 2021
Accepted: April 21, 2021
Published: April 23, 2021
https://doi.org/10.1021/acsmedchemlett.1c00127
© 2021 American Chemical Society
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M4K2009, M4K2117, and M4K2127.11 The structural
position of the 11C radionuclide was chosen based on
availability of the desmethyl precursors and ease of synthesis
(Figure 1). While there is no consensus for the ideal
a
Scheme 1. Radiosynthesis of 11C-Labeled Compounds
Figure 1. Structures of our lead 11C-radiotracers for ALK2.
physiochemical properties of small molecules that are BBB
penetrant,12 CNS Multiparameter Optimization (MPO) scores
offer a guideline for compound prioritization.13 Prior to
radiolabeling, CNS MPO desirability scores were calculated for
all of the lead compounds, giving scores of 4.34−5.04
(maximum score is 6.0), suggesting that all compounds are
rational leads as brain-penetrant radioligands. Calculated
logD7.4 values were also within the range for most brain-
penetrant PET radioligands14,15 (2.03−3.31), with limited off-
target binding. As such, none of the initially identified
compounds were excluded due to physiochemical character-
istics that would suggest low brain permeability (Table 1).
All radiosyntheses were performed on a commercial
automated carbon-11 synthesis unit for methylation reactions
(GE FX2 C). [11C]M4K2163 and [11C]M4K2009 were
synthesized by 11C-O-methylation with the “loop method”16,17
using [11C]CH3I and the respective phenolic precursors
(M4K2297 and M4K2298; see the Supporting Information
for their preparation) with <1 equiv of potassium tert-butoxide
(Scheme 1A). The radioligands were synthesized, isolated, and
formulated in radiochemical yields of 6−10% ([11C]-
M4K2163, n = 3) and 4−9% ([11C]M4K2009, n = 2) relative
to [11C]CO2. Both radiotracers were obtained in >95%
radiochemical purities and high molar activities ([11C]-
M4K2163: 270−350 GBq/μmol), [11C]M4K2009: 304
GBq/μmol). Small-scale vial-based radiosyntheses of [11C]-
M4K2117 and [11C]M4K2127 using [11C]CH3I and various
bases (KOtBu, NaOH, or TBAOH) resulted in low radio-
chemical conversion (<5%) by analytical HPLC and were not
further pursued. [11C]M4K2117 and [11C]M4K2127 were
each synthesized by 11C-N-methylation and also with use of
the “loop method”, although synthesis of these radioligands
employed the more reactive [11C]CH3OTf and the respective
N-desmethyl precursors (M4K2009 and M4K2043, Scheme
a
(A) O-methylations via [11C]CH3I, (B) N-methylations via [11C]-
CH3OTf.
1B). For the efficient radiolabeling of [11C]M4K2117, 1 equiv
of aqueous NaOH was added to the reaction mixture. These
radioligands were synthesized, isolated, and formulated in
radiochemical yields of 5−6% ([11C]M4K2117, n = 3) and
11−26% ([11C]M4K2127, n = 5) relative to [11C]CO2. Both
radiotracers were obtained in >99% radiochemical purities and
high molar activities ([11C]M4K2117: 269 GBq/μmol),
[11C]M4K2127: 132−664 GBq/μmol). All radiotracers were
prepared within 30−40 min from end of bombardment.
Shake-flask logD7.4 values were experimentally determined
using established procedures.18 Aliquots of the formulated
radiotracers were partitioned between octanol/phosphate
buffer, and the radioactivity in each layer was measured on a
γ counter. Experimental logD7.4 values were slightly higher
than the calculated values and were in the range of 2.45−3.37
(Table 1), consistent with most CNS PET tracers.14,15
The brain permeability of the radiotracers was then assessed
in healthy Sprague−Dawley rats (Figure 2). Rats were injected
(i.v.; tail-vein) with 16−23 MBq of each radiotracer, and
dynamic PET imaging was acquired over 90 min. Time-activity
Table 1. Physiochemical Properties of the Lead Compounds
a
b
c
c
c
d
e
ALK2 IC50 (nM)
B/P
pKa
clogP
clogD7.4
logD7.4
CNS MPO
M4K2009
M4K2117
M4K2127
M4K2163
13
7
9
0.9*
0.82
8.5
9.5
7.6
8.5
3.20
4.56
3.74
4.05
2.03
2.46
3.31
2.88
2.76 0.13
2.64 0.05
3.37 0.12
2.45 0.04
5.04
4.34
4.34
4.34
19
1.41
a
b
c
Cellular IC50.11 Brain/plasma ratio in female SCID mice (4 h) or *male SD-1 mice (2 h) @ 10 mg/kg PO.11 Properties retrieved from ACD/I-
d
e
Lab 2.0. Determined experimentally by shake-flask method with 11C-labeled compounds. Scored via an algorithm using a weighted scoring
function for clogP, clogD, molecular weight, topological polar surface area, HBDs, and pKa.
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Figure 2. (A) Summed (0−90 min, iterative reconstruction) PET images in transverse plane for the four 11C-radiotracers in male SD rats. (B)
Whole brain TACs for the radiotracers (0−90 min). (C) TACs for the pons for [11C]M4K2127 (0−90 min, n = 3).
curves (TACs) were extracted for whole brain and for the pons
as a region of interest using the atlas of Schwarz et al. 200619
implemented in VivoQuant (4.0patch1, Invicro). Three
tracers, [11C]M4K2163 (n = 2), [11C]M4K2117 (n = 1),
and [11C]M4K2009 (n = 1) showed relatively low brain
uptake, with peak SUV values of 1.1, 0.9, and 0.6, respectively,
within 1 min after injection. Fortunately, [11C]M4K2127 (n =
3) showed good permeability into the brain, with a peak SUV
of 1.8 0.2 for initial brain uptake within 1 min after injection,
followed by a moderate rate of wash out over 30 min.
Importantly, we found that [11C]M4K2127 has high uptake in
the pons (peak SUV = 2.0 0.3). Looking at the similar TACs
for [11C]M4K2127 in the pons and the whole brain, it is
evident the compound permeates homogeneously into the
pons as compared to the rest of the brain. This, importantly,
constitutes the first example of an ALK2 PET radiotracer and
provides evidence that compounds of this chemotype can
access the pons, which is the specific region of interest for the
treatment of DIPG tumors.
attributed to the lower pKa of the N-methyl piperazine moiety
in M4K2127 (Table 1) along with the molecule having a
reduced number of hydrogen bond donors (HBDs), a
parameter often associated with a decrease in permeability
glycoprotein (P-gp)-mediated efflux.12 Among the four lead
compounds, M4K2127 showed the lowest microsomal stability
(see the Supporting Information, Table S1), which is a
potential hurdle for further development as a drug candidate.
However, when administered via i.v. injection as in our rodent
PET imaging study, M4K2127 initially avoids major first-pass
metabolism by the liver which increases the initial Cmax.
These in vitro ADME results align well with the PET imaging
data demonstrating that [11C]M4K2127, having the best
permeability in vitro, efficiently crosses the BBB.
Herein, we present [11C]M4K2127 as an ALK2-targeting
radioligand that satisfactorily and homogeneously permeates
the brain. By employing an open science approach to this
work, we were able to rapidly radiolabel isotopologs of our lead
ALK2 inhibitors and apply PET imaging for the assessment of
brain penetration. The present study sheds light on our
previous work to establish B/P ratios in this new class of ALK2
inhibitors,11 with implications both for the drug development
process and direct analysis of DIPG-targeting drug candidates
in a clinical setting. To our knowledge, this report constitutes
the first disclosure of ALK2 PET radiotracers and efforts aimed
at assessing the degree of penetration into the brain (including
the pons) of a compound being pursued as a potential
treatment for DIPG.20
To investigate the properties that could be affecting the BBB
permeability of these four compounds, we reviewed their
Caco-2 permeability parameters as an indication of membrane
permeability as well as to consider the compounds as potential
substrates of efflux transporters. As anticipated from the PET
imaging results, M4K2127 had the highest Caco-2 perme-
ability, three times greater than that of M4K2009 (Papp AB
=
16.6 vs 5.4 × 10−6 cm/s where Papp > 3 indicates high
permeability). Additionally, the efflux ratio for M4K2127 was
found to be almost 2−3-fold better than that of M4K2009 and
M4K2163 (efflux ratio BA/AB = 0.9, 1.5, and 2.7, respectively;
see the Supporting Information, Table S1). This could be
While numerous compounds have entered the clinic for
DIPG, no studies on their degree of penetration into the pons
(using PET imaging, or any other method) have been
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reported. [11C]M4K2127 will be used as a biomarker to
further assist the drug development of 3,5-diphenylpyridine
ALK2 inhibitors. Blocking studies with [11C]M4K2127 to
confirm specific binding in the brain of rodents and higher
species, evaluation of radiometabolism, and effect of anesthesia
are planned. [11C]M4K2127 may also be used as a tool in
receptor occupancy, target engagement, and dosing regimens
for other ALK2 inhibitors as they progress toward the clinic.
M4K2297) and I.D.G.W. (M4K2298). Radiochemical tracer
compounds were designed, and their syntheses were devised
by E.M. and N.V. The precursor compounds were designed,
and their syntheses were devised by D.S. and I.D.G.W. Caco-2
HRMS and microsomal stability studies for M4K2127 were
conducted by T.K. Animal and imaging studies were
performed by J.T including image analysis. E.M., I.D.G.W.,
and N.V. conceived and initiated the project. All authors have
given approval to the final version of the manuscript.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acsmedchemlett.1c00127.
Funding
■
sı
N.V. thanks the Azrieli Foundation and the Canada Research
Chairs Program, Canada Foundation for Innovation, and the
Ontario Research Fund for support. The Ontario Institute for
Cancer Research (OICR) receives financial support from the
Government of Ontario through the Ministry of Training,
Colleges, and Universities.
Details for the synthesis and characterization of
M4K2127, M4K2117, M4K2297, and M4K2298; details
for the radiochemical synthesis and characterization of
[11C]M4K2009, [11C]M4K2117, [11C]M4K2127, and
[11C]M4K2163; protocols for logD7.4 measurement and
in vivo animal PET/MR imaging ADME parameters for
ALK2 inhibitors and ADME assay protocols (DOCX)
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
M4K Pharma Inc., functioning as a virtual biotech, serves as a
de facto hub for gathering and aligning the cooperation and
contributions of academic and industry partners into a drug
development program that operates free of restrictions on data
disclosure (i.e., no patents are filed). The authors thank the
scientific leadership of M4K Pharma, Dr. Aled M. Edwards, Dr.
Peter Ho, and Owen G. Roberts, for encouraging and
supporting our open science research collaboration. We
thank all members of the Azrieli Centre for Neuro-Radio-
chemistry and the CAMH Brain Health Imaging Centre for
support with the cyclotron, radiochemistry, methodology, and
imaging.
AUTHOR INFORMATION
Corresponding Authors
■
Iain D. G. Watson − Drug Discovery Program, Ontario
Institute for Cancer Research, M5G 0A3 Toronto, Ontario,
Canada; orcid.org/0000-0003-3508-3240;
Email: iain.watson@oicr.on.ca
Neil Vasdev − Azrieli Centre for Neuro-Radiochemistry, Brain
Health Imaging Centre, Centre for Addiction and Mental
Health (CAMH), M5T 1R8 Toronto, Ontario, Canada;
Department of Psychiatry, University of Toronto, M5T 1R8
Toronto, Ontario, Canada; orcid.org/0000-0002-2087-
5125; Email: neil.vasdev@utoronto.ca
ABBREVIATIONS
■
Authors
ADME, absorption distribution metabolism excretion; ALK2,
activin-like receptor 2; BBB, blood−brain barrier; B/P, total
brain-to-plasma ratio; CNS, central nervous system; DIPG,
diffuse intrinsic pontine glioma; HBD, hydrogen bond donor;
MPO, multiparameter optimization; PET, positron emission
tomography; rt, room temperature; SUV, standard uptake
value; TAC, time−activity curve
Emily Murrell − Azrieli Centre for Neuro-Radiochemistry,
Brain Health Imaging Centre, Centre for Addiction and
Mental Health (CAMH), M5T 1R8 Toronto, Ontario,
Canada
Junchao Tong − Azrieli Centre for Neuro-Radiochemistry,
Brain Health Imaging Centre, Centre for Addiction and
Mental Health (CAMH), M5T 1R8 Toronto, Ontario,
Canada
REFERENCES
David Smil − Drug Discovery Program, Ontario Institute for
Cancer Research, M5G 0A3 Toronto, Ontario, Canada;
orcid.org/0000-0002-6232-6087
■
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Author Contributions
The manuscript was written by E.M. and edited with D.S.,
I.D.G.W., and N.V., including contributions by all authors.
Radiochemical tracers were synthesized by E.M. with
precursors synthesized by D.S. (M4K2127, M4K2117, and
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