Radiosynthesis of [11C]LY2795050 for Preclinical and Clinical PET Imaging Using Cu(II)-Mediated Cyanation

Article abstract of DOI:10.1021/acsmedchemlett.8b00460

Copper-mediated ¹¹C-cyanation reactions have enabled the synthesis of PET radiotracers from a range of readily available precursors and avoid the need to use more toxic Pd catalysts. In this work we adapt our recently developed ¹¹C-c

Full text of DOI:10.1021/acsmedchemlett.8b00460

Letter
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Cite This: ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
11
Radiosynthesis of [ C]LY2795050 for Preclinical and Clinical PET
Imaging Using Cu(II)-Mediated Cyanation
†
,‡
†
§
‡
,§
Lingyun Yang, Allen F. Brooks, K,†atarina J. Makaravage, Huibin Zhang, Melanie S. Sanford,*
,
†
Peter J. H. Scott,* and Xia Shao*
†
Department of Radiology, University of Michigan, Ann Arbor, Michigan 48109, United States
‡
Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198,
P.R. China
§
Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109, United States
*
S Supporting Information
11
ABSTRACT: Copper-mediated C-cyanation reactions have enabled the synthesis of PET radiotracers from a range of readily
1
1
available precursors and avoid the need to use more toxic Pd catalysts. In this work we adapt our recently developed C-
1
1
cyanation of arylpinacolboronate (BPin) esters for the cGMP synthesis of [ C]LY2795050, a selective antagonist radiotracer
11
for the kappa opioid receptor (KOR). [ C]LY2795050 was synthesized in 6 ± 1% noncorrected radiochemical yield (based on
1
1
[
C]HCN, n = 3) using an automated synthesis module. Quality control testing confirmed the suitability of doses for
preclinical and clinical PET imaging (radiochemical purity >99%; specific activity >900 mCi/μmol; residual Cu < 0.1 μg/mL).
1
1
PET imaging was conducted in rodent and nonhuman primates, showing good brain uptake of [ C]LY2795050 and the
1
1
expected distribution of KOR. Analogous imaging with [ C]carfentanil (a selective mu opioid receptor (MOR) radiotracer)
revealed the anticipated regional differences in MOR and KOR distribution in the primate brain.
KEYWORDS: Positron emission tomography imaging, kappa opioid receptor, carbon-11, cyanation
pioid receptors are involved in a variety of neuro-
dependence. Since analgesia is associated with all of the opioid
receptor subtypes, but dependence and other side effects such
as respiratory depression are mostly attributed to mu receptors,
there is enormous interest in developing drugs (and PET
O
psychiatric diseases and remain popular targets for
1
imaging and drug development. These receptors were first
imaged in humans using positron emission tomography (PET)
2
10
in the 1980s. Since these early studies, significant work has
radiotracers) that are selective for the other opioid subtypes.
been undertaken to develop radiotracers for quantifying the
The kappa opioid receptor (KOR) structure has been recently
3
11
major opioid receptor subtypes (mu, delta, kappa, ORL-1).
revealed, and this is expected to spur development of new
12
Given that popular opioid pain killers such as morphine,
codeine, and fentanyl all act preferentially at mu opioid
drugs for this target. Reflecting this, our clinical colleagues
desire access to a KOR-selective PET radiotracer manufactured
according to current Good Manufacturing Practice (cGMP)
and suitable for clinical use.
4
,5
receptors (MORs), significant work has been undertaken to
understand the pharmacology of this receptor. For example, we
1
1
11
To date, several KOR antagonist radiotracers for PET
have used [ C]carfentanil ([ C]CFN) for decades with
1
3−20
6
imaging have been reported.
For clinical translation, we
selected [ C]LY2795050 ([ C]1) since it has high affinity (in
vitro K = 0.72 nM; in vivo K = 0.028 nM) and good
clinical colleagues to image the mu opioid system.
1
1
11
Mu opioid agonists are some of the most effective pain
7
killers used in modern medicine. However, the abuse of
i
d
20−23
selectivity for KOR (μ/κ = 11; δ/κ = 132).
the first evaluation of [ C]LY2795050 in human subjects
Furthermore,
opioids including prescription pain relievers, synthetic opioids,
and street drugs, has led to a serious crisis in the United
1
1
8
demonstrated the feasibility of using this radiotracer to image
States. The Centers for Disease Control estimate that about
7
2,000 Americans died of drug overdoses in 2017 alone, with
9
opioids implicated in 49,000 of these deaths. This crisis has
provided strong motivation to develop opioid painkillers
without undesirable side effects and that do not lead to
Received: October 3, 2018
Accepted: November 13, 2018
Published: November 13, 2018
©
XXXX American Chemical Society
A
DOI: 10.1021/acsmedchemlett.8b00460
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ACS Medicinal Chemistry Letters
Letter
2
0
KOR. However, all of the previously reported syntheses of
Scheme 2. Synthesis of Arylboronate Ester Precursor (6-
Bpin).
1
1
a
[
(
C]LY2795050 employed Pd-mediated cyanation reactions
Scheme 1A).
1
7−22
These are undesirable as Pd is expensive
11
Scheme 1. Inspiration for the Synthesis of [ C]LY2795050
1
1
via Cu-Mediated C-Cyanation
a
Reagents and conditions: (i) 2-chloro-1-fluoro-4-iodobenzene,
K CO , Cs CO , DMF, 12 h, 140 °C, 18%; (ii) (S)-3-(pyrrolidin-2-
2
4
2
3
2
3
(
Pd dba = $37,273/mol ) and has a relatively high toxicity
2 3
yl)pyridine, 1,2-DCE, 24 h, 65 °C; (iii) NaBH(OAc) , AcOH, 24 h,
3
with a low permitted daily exposure in drugs (≤10 μg/day for
65 °C, 85% (over 2 steps from 3); (iv) bis(pinacolato)diboron,
25
parenteral administration ).
Pd(dppf)Cl , KOAc, DMSO, 12 h, 85 °C, 65%.
2
Copper-mediated radiolabeling reactions represent an
attractive alternative to their palladium counterparts because
the catalysts are comparatively inexpensive (Cu(OTf)
=
duplicate this manual reaction by adding 1 M aqueous KOH
2
2
4
11
$
4,686/mol ), and Cu is significantly less toxic than Pd,
(0.2 mL) to the reactor to trap [ C]HCN and convert it to
1
1
reflected in a much higher permitted daily exposure limit
[ C]KCN. However, there was a marked decrease in RCC,
probably due to the deactivation of the Cu under strongly basic
conditions (entry 2). We next tested use of Pt wire coated with
2
5
26−30
(
≤340 μg/day for parenteral administration ). We
and
3
1−33
18
others
have recently shown that Cu-mediated F-
fluorination and C-cyanation reactions can be used to label
bioactive molecules from diverse aryl precursors with fluorine-
1
1
11
11
1 M KOH to trap [ C]HCN and convert it to [ C]KCN as
35
previously described, and obtained comparable conversion to
[ C]1 for the manual reaction (entry 3). This approach, while
effective, does require more time and steps than direct use of
[ C]HCN from the cyclotron, which is problematic when
considering the short half-life of C (20 min). If residual NH
11
1
8 and carbon-11, respectively. In this report, we describe the
1
1
automated cGMP production of [ C]LY2795050 doses
suitable for clinical use via the Cu-mediated cyanation of an
arylpinacolboronate (BPin) ester precursor with [ C]cyanide
1
1
11
11
3
3
4
(
Scheme 1B). With production batches in hand, we
were not detrimental to the labeling of 6-Bpin, we could
compared KOR distribution in nonhuman primates imaged
simplify and speed up the synthesis by removing the Pt wire
1
1
11
with [ C]LY2795050 to MOR distribution imaged with
and bubbling [ C]HCN directly into the reaction mixture.
1
1
11
[
C]CFN.
In our recent report of Cu-mediated C-cyanation reactions,
we demonstrated that a range of precursors were compatible
This proved to be the case, and bubbling [ C]HCN directly
11
into a solution of Cu(OTf) and pyridine (15 equiv) in DMA
2
(0.25 mL) demonstrated compatibility with NH . Conversion
3
30
11
with the method, including BPin esters. Thus, to explore the
to [ C]1 correlated with the equivalents of Cu utilized
1
1
radiosynthesis of [ C]LY2795050, we initially prepared
(entries 4−6). A further boost in RCC was achieved when Cu
1
1
arylboronate ester precursor (6-Bpin) as shown in Scheme
was added after [ C]HCN delivery (entries 7 and 8). The
2
. The condensation between 4-hydroxybenzaldehyde 2 and 2-
addition of exogenous H O (0.05 mL), which was beneficial
2
1
1
11
30
chloro-1-fluoro-4-iodobenzene afforded aldehyde 3 in 18%
yield. The aldehyde was converted to iminium 4 with (S)-3-
for C-cyanation with [ C]KCN in our previous work, was
1
1
not necessary for the synthesis of [ C]LY2795050 (entry 8),
likely because HCN is more soluble in DMA than KCN. Thus,
we moved forward using the method involving trapping with
pyridine in DMA (entry 7).
(
8
pyrrolidin-2-yl)pyridine, followed by reduction to form 5 in
5% yield from 3. The desired precursor 6-Bpin was then
obtained in 65% yield by treating 5 with bis(pinacolato)-
diboron. In order to confirm the identity of the radiolabeled
product, unlabeled LY2795050 reference standard was also
synthesized (see Supporting Information).
With an optimized radiosynthesis in hand, we next
automated the full synthesis, purification, and reformulation
1
1
of [ C]LY2795050 to qualify the method for cGMP
production of animal and clinical doses (Scheme 3). No
Initial manual labeling reactions were conducted to evaluate
11
11
the potential for labeling [ C]LY2795050 using a Cu-
carrier added [ C]HCN (∼800 mCi) was bubbled into a
1
1
mediated C-cyanation. One M KOH was used to trap
mixture of pyridine (15 equiv) in DMA (0.25 mL). Cu(OTf)
2
1
1
[
C]HCN, remove residual NH used in its production (since
(4 equiv) was then added, followed by 6-Bpin (1 equiv), and
the reaction was heated at 100 °C for 5 min to generate cyano
3
NH3 can be detrimental to downstream radiochemical
reactions), and convert it to [ C]KCN as previously
described. Small aliquots of this solution were subjected to
1
1
11
11
intermediate [ C]7. Hydrolysis to generate [ C]LY2795050
3
5
11
11
([ C]1) was accomplished by treating [ C]7 with 30% H O
2 2
our standard conditions (6-BPin, Cu(OTf) , and pyridine)
(0.2 mL) and 5.0 M NaOH (0.2 mL) at 80 °C for 5 min. The
reaction mixture was then diluted with acetic acid (0.4 mL)
and purified by semipreparative HPLC (column: Phenomenex
Prodigy C8, 10 μm, 150 × 10 mm; mobile phase: 25:75
MeCN:H O, 100 mM NH OAc, 1.0% acetic acid, pH = 4.8;
2
which, following hydrolysis with 30% H O and 5.0 M NaOH,
2
2
1
1
afforded 39% radiochemical conversion (RCC) to [ C]-
LY2795050 ([ C]1) (Table 1, entry 1). When we translated
1
1
this reaction to an automated synthesis module, we tried to
2
4
B
DOI: 10.1021/acsmedchemlett.8b00460
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ACS Medicinal Chemistry Letters
Letter
Table 1. Reaction Optimization Studies
a
Entry
Trapping Method
None
1 M KOH
Cu eq
RCC
b
1
2
3
4
5
6
7
8
2
2
2
2
3
4
4
4
39 ± 4%
5%
Pt wire coated with KOH
31%
20%
25%
30%
47%
50%
Cu(OTf) /pyridine in DMA
2
Cu(OTf) /pyridine in DMA
2
Cu(OTf) /pyridine in DMA
2
Pyridine in DMA
H O/pyridine in DMA
2
a
b
RCC = radiochemical conversion over 2 steps. n = 2.
11
Scheme 3. Radiosynthesis of [ C]LY2795050
UV = 254 nm, flow rate = 5.0 mL/min). The peak
Table 2. QC Data for Three Validation Runs
1
1
corresponding to [ C]LY2795050 (t ∼5−7 min, see Figure
R
QC Test
Specifications
Lot 1
Lot 2
Lot 3
S3 in the Supporting Information) was collected and
reformulated using a C18 solid-phase extraction cartridge to
Visual Inspection
pH
Clear, colorless, no ppt
4.5−7.5
Pass
5.0
Pass
5.0
>99
5.9
1.0
20.0
48
≤2.00
Pass
<0.1
Pass
5.0
>99
4.4
1.0
19.8
47
≤2.00
Pass
<0.1
11
afford formulated doses of [ C]LY2795050 (48 ± 10 mCi, n
3). The total synthesis time was approximately 45 min from
end-of-bombardment. The nondecay corrected radiochemical
RCP
Conc.
≥90%
≥3mCi/mL
>99
4.1
=
11
Radiochemical-ID RRT: 0.9−1.1
1.0
yield (RCY) was 6 ± 1%, based upon [ C]HCN. Radio-
Radionuclidic-ID
Filter integrity
Endotoxins
Sterility
Residual Cu
t1/2: 20 ± 2 min
Bubble point ≥45 psi
≤17.5 EU/mL
No microbial growth
<34 μg/mL
20.6
50
≤2.00
Pass
<0.1
chemical purity (RCP) was >99%, and specific activity was 914
±
97 mCi/μmol (n = 3). Doses from three validation runs
were submitted for quality control (QC) testing, and all doses
met or exceeded release criteria for clinical application at the
University of Michigan, including purity, sterility, and residual
solvent analysis (Table 2). Doses produced used Cu-mediated
reactions also need to be free of residual Cu if they are to be
used in the clinic. Samples from each of the qualification runs
were submitted for inductively coupled plasma mass
spectrometry (ICP-MS) analysis and were found to contain
residual Cu below the limit of quantification (<100 ppb), well
confirmed good brain uptake of the radiotracer and suitability
1
1
for in vivo imaging. Lastly, with access to both [ C]-
1
1
LY2795050 for KOR and [ C]CFN for MOR (prepared as
6
previously described ), we compared the regional brain
distribution of the two receptors in nonhuman primates
(Figure 1). PET imaging with both radiotracers was performed
in the same rhesus monkey, and regions-of-interest were
established and used to generate time-activity curves (TACs).
25
below the established limit for Cu.
With a qualified synthesis in hand, we next performed
11
preclinical PET imaging with [ C]LY2795050. Initial studies
were performed in rodents (see Supporting Information) and
1
1
[ C]LY2795050 displayed good brain uptake (peak SUV
C
DOI: 10.1021/acsmedchemlett.8b00460
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ACS Medicinal Chemistry Letters
Letter
1
1
11
Figure 1. Summed sagittal primate PET images of [ C]LY2795050 (A) and [ C]CFN (B) 0−60 min after injection of the radiotracer and
associated time-activity curves (C and D). (High resolution TACs are provided in the Supporting Information, see Figures S6 and S7).
∼
3.5−4.5 min in selected brain regions) and a heterogeneous
spectra and HRMS for other known compounds
synthesized; procedures and HPLC chromatograms for
radiochemical syntheses and quality control; protocols
for animal PET imaging studies. (PDF)
distribution pattern (striatum > cortex ∼ thalamus >
cerebellum), consistent with previous reports of KOR
36
distribution in nonhuman primates. MOR imaging with
1
1
[
C]CFN revealed different distribution. After the fast initial
uptake (peak SUV at 6.25−8.75 min in selected regions),
AUTHOR INFORMATION
Corresponding Authors
E-mail: mssanfor@umich.edu.
E-mail: pjhscott@umich.edu.
E-mail: xshao@umich.edu.
1
1
■
[
C]CFN uptake in cerebellum washed out gradually, but the
tracer was retained well in striatum, thalamus, and pons. The
*
*
*
1
1
difference between imaging with [ C]LY2795050 and
1
1
[
C]CFN is consistent with the differences in distribution of
36−39
KOR and MOR in the primate brain.
ORCID
In summary, we report the first validation of our Cu-
mediated cyanation of BPin esters for the cGMP synthesis of a
PET radiotracer for preclinical and clinical applications. The
Allen F. Brooks: 0000-0003-3773-3024
Katarina J. Makaravage: 0000-0002-1225-5305
Melanie S. Sanford: 0000-0001-9342-9436
Peter J. H. Scott: 0000-0002-6505-0450
Xia Shao: 0000-0002-7291-2477
1
1
synthesis of [ C]LY2795050, a PET radiotracer for the KOR,
was fully automated using a commercial radiochemistry
synthesis module. Doses met all QC criteria for preclinical
and clinical use and were used to image rodents and
Author Contributions
11
nonhuman primates. Comparison with [ C]CFN imaging of
MOR identified regional brain distribution differences
consistent with the known distribution of opioid receptors in
primates. We expect to initiate clinical imaging studies with
The manuscript was written through contributions of all
authors and all authors have given approval to the final version
of the manuscript.
Funding
1
1
[
C]LY2795050 in the near future.
This work was supported by NIH (R01EB021155, M.S.S. and
P.J.H.S.) and the China Scholarship Council (201607060008,
L.Y. and P.J.H.S.).
ASSOCIATED CONTENT
* Supporting Information
■
S
Notes
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acsmedchem-
lett.8b00460.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Full experimental details; copies of H NMR and 13C
1
The authors thank Jenelle Stauff, Janna Arteaga, and Phillip
Sherman for conducting animal studies and Bradford
Henderson for assistance with QC testing.
NMR spectra, as well as HRMS, for novel and/or key
1
compounds (1, 6-BPin and 6-SnMe ); copies of NMR
3
D
DOI: 10.1021/acsmedchemlett.8b00460
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ACS Medicinal Chemistry Letters
Letter
Radiotracer: Synthesis and In Vivo Evaluation of 18F-LY2459989 in
ABBREVIATIONS
■
Nonhuman Primates. J. Nucl. Med. 2018, 59, 140−146.
CFN, carfentanil; 1,2-DCE, 1,2-dichloroethane; DMA, N,N-
dimethylacetamide; DMF, N,N-dimethylformamide; DMSO,
dimethyl sulfoxide; DOR, delta opioid receptor; HPLC, high-
performance liquid chromatography; KOR, kappa opioid
receptor; MOR, mu opioid receptor; RCC, radiochemical
conversion; RCP, radiochemical purity; RCY, radiochemical
yield; ROI, regions-of-interest; SUV, standardized uptake
value; PET, positron emission tomography.
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