Synthesis and in-vivo evaluation of [11C]p-PVP-MEMA as a PET radioligand for imaging nicotinic receptors

Article abstract of DOI:10.1071/CH08083

Within the class of (4-pyridinyl)vinylpyridines developed by Abbott laboratories as potent neuronal nicotinic acetylcholine receptor ligands, p-PVP-MEMA ({(R)-2-[6-chloro-5-((E)-2-pyridin-4-ylvinyl)pyridin-3-yloxy]-1- methylethyl}methylamine) is the lead compound of a novel series that do not display the traditional nicotinic-like pyrrole-ring but still possessing high subnanomolar affinity (K_i 0.077 nm?displacement of [ ³H](?)cytisine from whole rat brain synaptic membranes). In the present study, p-PVP-MEMA and its nor-derivative ({(R)-2-[6-chloro-5-((E)-2- pyridin-4-ylvinyl)pyridin-3-yloxy]-1-methylethyl}methylamine) as precursor for labelling with the short-lived positron-emitter carbon-11 (T_1/2 20.4 min) were synthesized in 10 chemical steps from 2-hydroxy-5-nitropyridine and Boc-d-alanine. N-Alkylation of nor-p-PVP-MEMA with [¹¹C]methyl iodide afforded [¹¹C]p-PVP-MEMA (>98% radiochemically pure, specific activity of 86.4 GBq ?mol^?1) in 2% (non-decay corrected and non-optimized) radiochemical yield, in 34 min (including HPLC purification and formulation). Preliminary positron emission tomography (PET) results obtained in a Papio hamadryas baboon showed that [¹¹C]p-PVP-MEMA is not a suitable PET-radioligand. CSIRO 2008.

Full text of DOI:10.1071/CH08083

Full Paper
CSIRO PUBLISHING
Aust. J. Chem. 2008, 61, 438–445
www.publish.csiro.au/journals/ajc
Synthesis and In-Vivo Evaluation of [11C]p-PVP-MEMA
as a PET Radioligand for Imaging Nicotinic Receptors
Frédéric Dollé,A Sandrine Langle,A Gaëlle Roger,A Roger R. Fulton,B
Béatrice Lagnel-de Bruin,A David J. Henderson,B Françoise Hinnen,A
Taliesha Paine,C Mark J. Coster,D Heric Valette,A Michel Bottlaender,A
and Michael KassiouC,E,F,G
ACEA, Service Hospitalier Frédéric Joliot, Institut d’Imagerie Biomédicale,
4 Place du Général Leclerc, F-91401 Orsay, France.
BDepartment of PET and Nuclear Medicine, Royal Prince Alfred Hospital,
Missenden Road, Camperdown, NSW 2050, Australia.
CSchool of Chemistry, University of Sydney, NSW 2006, Australia.
DEskitis Institute for Cell and Molecular Therapies, Griffith University, Don Young Rd,
Nathan, Qld 4121, Australia.
EDiscipline of Medical Radiation Sciences, University of Sydney, NSW 2006, Australia.
FBrain and Mind Research Institute, 100 Mallett St, Camperdown, NSW 2050, Australia.
GCorresponding author. Email: m.kassiou@usyd.edu.au
Within the class of (4-pyridinyl)vinylpyridines developed by Abbott laboratories as potent neuronal nico-
tinic acetylcholine receptor ligands, p-PVP-MEMA ({(R)-2-[6-chloro-5-((E)-2-pyridin-4-ylvinyl)pyridin-3-yloxy]-1-
methylethyl}methylamine) is the lead compound of a novel series that do not display the traditional nicotinic-like
pyrrole-ring but still possessing high subnanomolar affinity (Ki 0.077 nm—displacement of [3H](−)cytisine from whole rat
brain synaptic membranes). In the present study, p-PVP-MEMA and its nor-derivative ({(R)-2-[6-chloro-5-((E)-2-pyridin-
4-ylvinyl)pyridin-3-yloxy]-1-methylethyl}methylamine) as precursor for labelling with the short-lived positron-emitter
carbon-11 (T1/2 20.4 min) were synthesized in 10 chemical steps from 2-hydroxy-5-nitropyridine and Boc-d-alanine.
N-Alkylation of nor-p-PVP-MEMA with [11C]methyl iodide afforded [11C]p-PVP-MEMA (>98% radiochemically pure,
specific activity of 86.4 GBq µmol−1) in 2% (non-decay corrected and non-optimized) radiochemical yield, in 34 min
(including HPLC purification and formulation). Preliminary positron emission tomography (PET) results obtained in a
Papio hamadryas baboon showed that [11C]p-PVP-MEMA is not a suitable PET-radioligand.
Manuscript received: 27 February 2008.
Final version: 22 April 2008.
1. Introduction
of nAChRs is found not only in Alzheimer’s disease, but also
in Parkinson’s disease, Lewy body dementia, and progressive
supranuclear palsy.[5]
Nicotinic receptors play an important role in complex brain func-
tions, such as learning and memory, and they are also involved in
the pathogenesis of several brain disorders, such as Alzheimer’s
disease, Parkinson’s disease, Tourette’s syndrome, schizophre-
nia, depression, and attention deficit/hyperactivity disorder.[1–3]
It is without dispute that dementia is an increasingly impor-
tant health problem in this century. Alzheimer’s disease is the
most common type of dementia, but frontotemporal and diffuse
Lewy body disease are increasingly being recognized as impor-
tant causes of dementia. Nicotinic cholinergic mechanisms may
be important in explaining the pathophysiology and in design-
ing treatments for Alzheimer’s disease.[4] Postmortem studies
have shown that patients who have Alzheimer’s disease have a
marked reduction in neuronal nicotinic acetylcholine receptors
(nAChRs) compared with age-matched controls. These losses
have been attributed to the major brain nAChR subtype α4β2 and
mayreflect, inpart, thelossofpresynapticreceptorsfromcholin-
ergic forebrain neurones and their terminal processes.[5] The loss
Important progress in the knowledge of the structure and
properties of brain nAChRs has been achieved over the past
decade. However, the mechanisms by which they contribute
to the pathogenesis of various neuropsychiatric disorders still
remain largely unknown.The introduction of non-invasive imag-
ing techniques, such as positron emission tomography (PET) has
made possible the study of neuroreceptors in living subjects.
Studies of the localization and quantification of these recep-
tors can offer insight into their status in normal and disease states
only when suitable radioligands are developed.[6–8] To this end
a tremendous amount of effort has focussed on analogues of
the alkaloid epibatidine (Fig. 1), resulting in the development
of several radioligands labelled with either carbon-11 (half-
life 20.4 min), fluorine-18 (half-life 109.8 min), and bromine-76
(half-life 16.2 h).[9–18] Although most of these showed brain dis-
tribution and in vivo pharmacological characteristics suitable
© CSIRO 2008
10.1071/CH08083
0004-9425/08/060438

[
11C]p-PVP-MEMA as a PET Radioligand
439
R2
possesses superior imaging properties to the tertiary amine
pyrrolidineanalogue[11C]methyl-p-PVC.Theaimofthepresent
study was to label p-PVP-MEMA with carbon-11 and perform
preliminary in vivo assessment in a baboon using PET.
R1
N
X
N
11CH3
O
N
N
(
)
n
[
11C]A-84543
n
R1 R2
X
2. Results and Discussion
Epibatidine
1
H
11CH3
Me
H
H
Cl
2.1. Chemistry
1
1
1
1
[
11C]Me-EP
H
H
Cl
18F
18F
18F
18F
18Br
[
18F]FEP
The syntheses of p-PVP-MEMA 1 and its corresponding nor-
methyl derivative 14, as a precursor for carbon-11 labelling, are
outlined in Schemes 1–3. 2-Chloro-5-hydroxy-3-iodopyridine
7 was obtained in six steps and 30% overall yield from
commercially available 2-hydroxy-5-nitropyridine 2. Briefly,
iodination of 2 with iodine and sodium carbonate in N,N-
dimethylformamide (DMF) at 80◦C for 8 h gave the iodopyridine
3 in 59% yield. Chlorination of 3 was performed at 120◦C for 2 h
using phosphoryl chloride in quinoline and yielded the chloropy-
ridine 4 in 96% yield. Reduction of the nitro function, performed
at 70◦C for 1 h using iron powder in a 2/3 mixture (v/v) of water
and glacial acetic acid, afforded the aminopyridine 5 in 91%
yield. Substitution of the amino-function by an acetoxy function
was performed using the following two-step sequence: (i) reac-
tion of 5 at 0◦C for 1 h in 48% aqueous tetrafluoroboric acid
and aqueous sodium nitrite, followed by filtration of the reac-
tion product; and (ii) reaction in acetic anhydride of the obtained
crude solid for 1 h at 80◦C. 5-Acetoxy-2-chloro-3-iodopyridine
6 was readily obtained in 67% yield and immediately hydrolyzed
at room temperature with aq. 2 N potassium hydroxide for 24 h
to give the hydroxypyridine 7 in 88% yield (Scheme 1).
N
H
O
[
18F]FPhEP
Ph
FPh
H
N
H
[
18F]F2PhEP
18F]FhEP
76Br]BEP
18F
H
H
[
2
1
2-[18F]F-A-85380
H
[
R3
11C]methyl-p-PVC Cl
R4
(Z)
[
N
O
R4
N
[
11C]ZW-90
11C]ZW-110
H
H
(CH2)4OH
(CH2)4F
11CH3
N
R3
[
H
11CH3
N
N
O
Me
[
11C]p-PVP-MEMA ([11C]-1)
N
Cl
Fig. 1. Selected nicotinic acetylcholine receptor molecules including
p-PVP-MEMA 1.
N-Boc-d-alanine 8 was reduced with borane tetrahydrofuran
complex (1 m in tetrahydrofuran) at 0◦C during 2 h to give the
corresponding alcohol 9 in 89% yield (Scheme 2). Mitsunobu
couplingof 9andthehydroxypyridine 7 usingdiisopropylazodi-
carboxylate (1.2 equiv.) and triphenylphosphine (1.2 equiv.) in
tetrahydrofuran at room temperature for 24 h gave the ether 10
in a moderate yield of 40%. N-Methylation of derivative 10 was
performed using methyl iodide and sodium hydride in DMF at
room temperature for 18 h and afforded 11 in 94% yield.
Palladium-catalyzed Heck-type coupling of compounds 10
and 11 with 4-vinylpyridine, using palladium acetate as the
catalyst, in acetonitrile that contained tri(o-tolyl)phosphine
and diisopropylamine at 95◦C for 3 h gave the corresponding
2-pyridin-4-ylvinylpyridines 12 and 13 in 45 and 48% yield,
respectively (Scheme 3). Finally, N-Boc removal was performed
with trifluoroacetic acid in dichloromethane (1/5, v/v) at room
temperature for 15 min and cleanly gave the amines 14 and 1 in
98 and 93% yield, respectively.
for imaging nAChRs,[19–23] their toxicity as a result of subtype
non-selectivity prohibited their use in humans.[24]
During the same period a series of 3-pyridyl ether compounds
that possess subnanomolar affinity for brain nAChRs with an
ability to differentially activate subtypes of neuronal nAChRs
were described.[25] Of these compounds the pyrrolidine-based
ligand, A-84543 (Ki 0.15 nm) (Fig. 1) was the first to be
labelled from this series with carbon-11.[26] This derivative,
which only showed moderate specific binding to nAChRs in vivo
in mice and baboon,[27,28] opened the route to the design of
several novel analogues, such as the azetidinyl-based fluoropy-
ridine 2-[18F]F-A-85380,[29–31] which is currently the only PET
probe used in humans for quantitative brain imaging of the
nAChRs.[32–35] More recently analogues of A-84543, such as
ZW-90/ZW-110[36,37] and methyl-p-PVC,[38] have been labelled
using carbon-11. All of them have been evaluated in non-human
primates using PET, but of particular interest was [11C]methyl-
p-PVC, a compound that displays a high in vitro nAChR binding
(Ki 56 pm) and shown to be suitable for studying nAChR
occupancy using endogenous and exogenous ligands.[39]
Further structure–activity relationship studies from this
series (performed by Abbott laboratories) have identified struc-
tures that do not display the traditional nicotinic-like cyclic
pyrrolidine or azetidine motif but still retain a high affin-
ity for nAChRs.[40] One of the lead members from this
series, {(R)-2-[6-chloro-5-((E)-2-pyridin-4-ylvinyl)pyridin-3-
yloxy]-1-methylethyl}methylamine (p-PVP-MEMA, 1, Fig. 1),
possesses high affinity for nAChRs (Ki 77 pm)[40] and also con-
tains a methylamino moiety amenable to radiolabelling using
carbon-11 (Fig. 1). This represents an interesting lead molecule
as it contains a secondary amine that is in line with the most
successful nAChR ligand, 2-[18F]F-A-85380, and therefore may
2.2. Radiochemistry
p-PVP-MEMA 1 was labelled with carbon-11 (T1/2 20.4 min)
using [11C]methyl iodide from the corresponding nor-methyl
derivative 14 by N-methylation (Scheme 4). [11C]Methyl iodide
was synthesized from cyclotron-produced [11C]carbon dioxide,
trapped in an DMF solution that contained 14 and tetra-n-
butylammonium hydroxide and allowed to react at room tem-
perature for 2 min, followed by heating at 80◦C for 5 min. The
reaction mixture was purified by reverse phase semi-preparative
HPLC. This afforded [11C]-1 in 2% (n = 4) non-decay corrected
radiochemical yield, based on starting [11C]methyl iodide, in
an average synthesis time of 34 min (including HPLC purifi-
cation and formulation). Co-injection of the non-radioactive 1
was performed using analytical HPLC to confirm the identity
of the product. In the final product solution, radiochemical and

440
F. Dollé et al.
O2N
O2N
I
O2N
I
I2
POCl3
Na2CO3, DMF
80°C, 8h
59%
Quinoline
120°C, 2h
96%
N
OH
N
OH
N
Cl
2
3
4
(1) HBF4, NaNO2
AcO
I
H2N
I
HO
I
KOH
Fe
H2O, 0°C, 1h
H2O, AcOH
70°C, 1h
91%
(2) Ac2O
80°C, 1h
67%
rt, 24h
88%
N
Cl
N
Cl
N
Cl
6
7
5
Scheme 1. Synthesis of 2-chloro-5-hydroxy-3-iodopyridine 7.
HO
I
NHBoc
O
NHBoc
CO2H
NHBoc
OH
N
Cl
BH3·THF
I
7
THF
0°C, 2h
89%
DIAD, PPh3
THF
rt, 24h
40%
10
N
Cl
9
8
NMeBoc
O
CH3I
NaH, DMF
I
rt, 18h
94%
N
Cl
11
Scheme 2. Synthesis of [(R)-2-(6-chloro-5-iodopyridin-3-yloxy)-1-methylethyl]methylcarbamic acid tert-butyl ester 11.
Figure 2a shows the time activity curves obtained in the thala-
mus (-ꢀ-) and the cerebellum (-ꢁ-), regions known to contain
the highest and lowest density of nAChRs respectively. Brain
uptake of [11C]-1 reached maximal uptake after 2 min (0.4–0.6%
of injected dose per 100 mL of tissue (% I.D. 100 mL−1)) and
stayed at approximately the same uptake level for the remain-
ing 58 min of imaging for both structures. Figure 2b illustrates
in a slice containing the thalamus the poor brain penetration of
[11C]-1.As a result of similar uptake in both regions, the index of
specific binding determined as the ratio of thalamus over cere-
bellum was ∼1 throughout the time course of the experiment. In
contrast, [11C]methyl-p-PVC in rhesus monkey has been shown
to display a thalamus to cerebellum ratio of around 1.5 at 20 min
post-injection, which increases to 4.5 at 90 min.[39]
NRBoc
NRBoc
O
N
O
I
N
Pd(OAc)2, P(o-tolyl)3
(i-Pr)2NH, CH3CN
95°C, 3h
N
Cl
N
Cl
R ϭ H (10)
R ϭ Me (11)
R ϭ H (12)
R ϭ Me (13)
45–48%
NHR
O
N
TFA, CH2Cl2
rt, 15min
93–98%
R ϭ H (14)
R ϭ Me (1) (p-PVP-MEMA)
N
Cl
Scheme 3. Synthesis of nor-p-PVP-MEMA 14 and p-PVP-MEMA 1.
3. Conclusion
chemical purity was greater than 98% with a specific activity
of 86.4 GBq µmol−1 (2.33 Ci µmol−1). No attempts were made
to optimize these conditions as sufficient quantities of the radi-
oligand were produced to enable preliminary pharmacological
evaluation.
Formulation of labelled product for intravenous injection was
achieved using the following sequence: (i) evaporation of HPLC
solvent; (ii) reconstitution of residue in water for injections
(4 mL); and (iii) sterile filtration through a 0.22 µm filter. The
final injectable solution was clear and colourless with a pH of
7.0. The preparation was free from starting labelling precursor
14. Administration to the animal was performed within 10 min
following the end of synthesis.
In this study, p-PVP-MEMA 1, a chemically closely related
structure to methyl-p-PVC without containing the cyclic pyrro-
lidine moiety was synthesized, radiolabelled with carbon-11,
and evaluated in a baboon using PET. [11C]-1 was prepared by
N-alkylation of the nor-methyl derivative 14 with [11C]methyl
iodide in reproducible yields and specific radioactivities. The
preliminary results from a single PET imaging study revealed
that [11C]-1 uptake in the baboon brain was homogeneous with
no amplification in regions known to contain a high density of
nAChRs. There are several possible reasons for this observation
includingthemetabolicstabilityof[11C]-1.Althoughthishasnot
been measured it is possible that [11C]-1 is rapidly metabolized
in blood or other peripheral tissue before entering the central ner-
vous system (CNS).Another possible explanation is that [11C]-1
could also be a substrate for P-glycoprotein (P-gp) and prevents
its entry into the CNS. Another less likely explanation is the
lipophilicity (log P) of [11C]-1. It has been reported that CNS lig-
ands should posses a log P of between 2 and 3.5 for maximal CNS
penetration. [11C]-1 possesses a calculated log P of 2.8 which
2.3. Evaluation using PET
Thein-vivouptakeof[11C]-1wasexaminedusingPETinaPapio
hamadryas baboon. Dynamic PET brain imaging commenced
just before intravenous administration of [11C]-1 (100 MBq
in 4 mL of saline) and was terminated 60 min post injection.

[
11C]p-PVP-MEMA as a PET Radioligand
441
11CH3
H
(1) [11C]CH3I
NH2
O
N
N
N
O
DMF/TBAH
80°C, 5min
N
Cl
N
Cl
(2) HPLC purification
[
11C]p-PVP-MEMA ([11C]-1)
14
Scheme 4. Radiosynthesis of [11C]p-PVP-MEMA [11C]-1.
(a)
(b)
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Thalamus
Cerebellum
0
5
10 15 20 25 30 35 40 45 50 55 60
Time [min]
Fig. 2. PET imaging of [11C]p-PVP-MEMA [11C]-1 in a Papio hamadryas baboon. (a) Time activity curves of [11C]-1 in the thalamus (-ꢀ-, a nAChR-rich
region) and the cerebellum (-ꢁ-, a nAChR-poor region), (b) Activity distribution in a slice containing the thalamus (at 30–60 min).
would suggest that it is within the expected range. However,
a comprehensive theory of the relationship between lipophilic-
ity and imaging characteristics for nAChR radioligands remains
to be developed. In spite of its subnanomolar in-vitro affinity
for nAChRs, p-PVP-MEMA 1 does not possess the required
properties for studying nAChRs in the brain using PET.
solvents (CD2Cl2, δ 5.32; CDCl3, δ 7.24; (D6)acetone, δ 2.05)
and/or TMS as internal standards for 1H NMR spectra as well as
the deuterated solvents (CD2Cl2, δ 53.8; CDCl3, δ 77.2) and/or
TMS as internal standards for 13C NMR spectra. Chemical shifts
arereportedinppm, downfieldfromTMS(s, d, t, dd, m, andbrfor
singlet, doublet, triplet, doublet of doublet, multiplet, and broad,
respectively). Mass spectra (MS), DCI/NH+4 , were measured on
a Thermo-Finnigan LCQ Deca XP+ apparatus.
4. Experimental
4.1. General
4.2. Chemistry
4.1.1. Chemicals, TLC, and HPLC
2-Hydroxy-3-iodo-5-nitropyridine 3
Chemicals were purchased from Aldrich, Fluka, or Sigma
France and were used without further purification. TLCs were
run on pre-coated plates of silica gel 60F254 (Merck). The
compounds were visualized when possible at 254 nm using a
UV-lamp and/or by dipping the TLC plates in a 1% ethano-
lic ninhydrin solution and heating on a hot plate. HPLCs were
performed using the following columns and conditions: HPLC
A: semi-preparative column, Symmetry C18 (300 × 7.8 mm,
7 µm); eluent 70/30/0.1 (v/v/v) acetonitrile/water/NEt3; flow
rate 7.0 mL min−1. HPLC B: semipreparative X-Terra RP
C18 column (300 × 7.8 mm, 10 µm); eluent 30/70 (v/v) ace-
tonitrile/0.1 m aq. NH4OAc (adjusted to pH 10); flow rate
6.0 mL min−1. HPLC C: analytical X-Terra RP C18 column
(150 × 4.6 mm, 5 µm); eluent 20/80 (v/v) acetonitrile/0.1 m aq.
2-Hydroxy-5-nitropyridine 2 (14.0 g, 0.1 mol, MW 140.10)
and Na2CO3 (11.0 g, 0.1 mol, 1 equiv., MW 105.99) were dis-
solved in 100 mL of DMF. Iodine (25.3 g, 0.1 mol, 1 equiv., MW
253.81) was added over 3 min and the reaction mixture was
then heated at 80◦C for 8 h. The final dark reaction mixture was
rotary evaporated to one-half of its initial volume, cooled to room
temperature, diluted with water, and filtered. The solution was
then made acidic (pH 5) with glacial acetic acid. The resulting
yellow solid was filtered off and dried under vacuum to give
15.8 g (59%) of 2-hydroxy-3-iodo-5-nitropyridine 3. RF 0.30
(heptane/EtOAc, 1/1 (v/v)). δH ((D6)acetone, 298 K) 8.82 (d, J
1.5, 1H), 8.75 (d, J 1.6, 1H). δC ((D6)acetone, 298 K) 167.7 (C),
163.7 (C), 143.4 (CH), 138.5 (CH), 95.0 (C). m/z (C5H3IN2O3):
267 [M + H]+.
NH4OAc (adjusted to pH 7); flow rate 2.0 mL min−1
.
2-Chloro-3-iodo-5-nitropyridine 4
4.1.2. Spectroscopy
Compound 3 (12.8 g, 48.1 mmol, MW 265.99) dissolved in
6 mL of DMF was added to quinoline (2.9 mL, 24.4 mmol, 0.5
equiv., MW 129.16, d 1.093). The reaction flask was cooled
NMR spectra were recorded on a Bruker Avance 400 MHz
apparatus using the hydrogenated residue of the deuterated

442
F. Dollé et al.
to 5◦C, and phosphoryl chloride (4.5 mL, 48.3 mmol, 1 equiv.,
MW 153.33, d 1.645) was added dropwise. The mixture was
blanketed with argon and heated at 120◦C for 2 h. The mixture
was then cooled to room temperature and 15 mL of water added.
The mixture was cooled to 0◦C and the resulting brown solid was
filtered off. Recrystallization from ethanol gave 13.1 g (96%) of
2-chloro-3-iodo-5-nitropyridine 4 as a pale brown solid. RF 0.76
(heptane/EtOAc, 1/1 (v/v)). δH (CDCl3, 298 K) 9.17 (d, J 1.2,
1H), 8.89 (d, J 1.2, 1H). δC (CD2Cl2, 298 K) 160.6 (C), 144.5
(CH), 144.0 (CH), 143.0 (C), 95.0 (C). m/z (C5H2ClIN2O2): 287
[M + H]+, 285 [M + H]+.
(10.0 g, 52.8 mmol, MW 189.21) in 50 mL of THF. The addi-
tion occurred over 30 min, and then the reaction mixture was
stirred for another 2 h at 0◦C. The reaction was quenched with
water and the solution was extracted three times with EtOAc.
The organic layers were collected, washed with 100 mL of
water and 100 mL of brine, dried over anhydrous MgSO4 and
concentrated to dryness to give 8.2 g (89%) of ((R)-2-hydroxy-
1-methylethyl)carbamicacidtert-butylester 9asacolourlessoil.
The solid was used without further purification. RF 0.27 (hep-
tane/EtOAc, 1/1 (v/v)). δH (CD2Cl2, 298 K) 4.70 (br, 1H), 3.72
(br m, 1H), 3.57 (dd, J 15.2 and 4.0, 1H), 3.47 (dd, J 10.8 and
6.4, 1H), 1.44 (s, 9H), 1.12 (d, J 6.8, 3H). δC (CD2Cl2, 298 K)
157.0 (C), 80.0 (C), 67.2 (CH2), 49.2 (CH), 28.9 (3 × CH3), 17.9
(CH3). m/z (C8H17NO3): 176 [M + H]+.
5-Amino-2-chloro-3-iodopyridine 5
Compound 4 (1.03 g, 3.6 mmol, MW 284.44) was added to a
mixture of water (10 mL) and glacial acetic acid (15 mL). Iron
powder (849 mg, 15.2 mmol, 4.2 equiv., MW 55.85) was then
added to the reaction flask and the mixture was heated for 1 h
at 70◦C. Once cooled to room temperature, the reaction mixture
was diluted with water, and then potassium hydroxide pellets
were added until the pH reached >8. The mixture was extracted
withEtOAcandtheextractevaporatedtodrynesstoyield841 mg
(91%) of 5-amino-2-chloro-3-iodopyridine 5 as a yellow solid.
RF 0.46 (heptane/EtOAc, 1/1 (v/v)). δH (CD2Cl2, 298 K) 7.78
(d, J 1.2, 1H), 7.48 (d, J 1.2, 1H), 3.86 (br s, 2H). δC (CD2Cl2,
298 K) 157.8 (C), 136.1 (CH), 134.2 (CH), 133.3 (C), 94.5 (C).
m/z (C5H4ClIN2): 257 [M + H]+, 255 [M + H]+.
[(R)-2-(6-Chloro-5-iodo-pyridin-3-yloxy)-1-
methylethyl]carbamic Acid tert-Butyl Ester 10
Diisopropylazodicarboxylate(0.43 mL, 2.2 mmol, 1.2equiv.,
MW 202.21, d 1.027) and triphenylphosphine (568 mg,
2.2 mmol, 1.2 equiv., MW 262.29) were dissolved in 5 mL of
THF at 0◦C under argon. Compound 9 (316 mg, 1.8 mmol, MW
175.23) and 2-chloro-5-hydroxy-3-iodopyridine (7) (553 mg,
2.2 mmol, 1.2 equiv., MW 255.44) were added to the reac-
tion flask, and the mixture was stirred at room temperature
for 24 h. The solvent was evaporated and the crude oil was
chromatographed on silica gel using heptane/EtOAc (9/1 to
7/3) to afford 297 mg (40%) of [(R)-2-(6-chloro-5-iodo-pyridin-
3-yloxy)-1-methylethyl]carbamic acid tert-butyl ester 10 as a
yellow oil. RF 0.65 (heptane/EtOAc, 1/1 (v/v)). δH (CD2Cl2,
298 K) 8.03 (d, J 3.1, 1H), 7.71 (d, J 2.4, 1H), 5.04 (br s, 1H),
4.05–3.85 (m, 3H), 1.41 (s, 9H), 1.24 (d, J 6.7, 3H). δC (CD2Cl2,
298 K) 155.4 (C), 154.1 (C), 145.7 (C), 136.8 (CH), 134.6 (CH),
94.3 (C), 79.5 (C), 72.3 (CH2), 45.9 (CH), 28.5 (3 × CH3), 17.7
(CH3). m/z (C13H18ClIN2O3): 415 [M + H+], 413 [M + H]+.
5-Acetoxy-2-chloro-3-iodopyridine 6
Compound 5 (52.0 g, 7.9 mmol, MW 254.46) was dissolved
in 11.4 mL of aq. HBF4 at 0◦C. A solution of sodium nitrite
(596 mg, 8.6 mmol, 1.1 equiv., MW 69.00) dissolved in 3 mL
of water was then added dropwise at 0◦C, and the mixture was
stirred for another 1 h at 0◦C.The resulting solid was filtered off,
washed with Et2O, air-dried, and redissolved in 9.4 mL of acetic
anhydride. The reaction mixture was heated for 1 h at 80◦C,
cooled to room temperature, diluted with EtOH (10 mL), and
then concentrated to dryness. EtOH (10 mL) was added again
andthemixtureconcentratedoncemoretodryness.Theresulting
solid was dissolved in Et2O. The organic solution was washed
with water, dried with MgSO4, and concentrated to give 1.57 g
(67%) of 5-acetoxy-2-chloro-3-iodopyridine 6 as a pale yellow
oil. RF 0.66 (heptane/EtOAc, 1/1 (v/v)). δH (CD2Cl2, 298 K)
8.20 (d, J 1.5, 1H), 7.99 (d, J 1.5, 1H), 2.30 (s, 3H). δC (CD2Cl2,
298 K) 168.7 (C), 150.9 (C), 145.8 (C), 142.5 (CH), 142.3 (CH),
93.9 (C), 21.0 (CH3). m/z (C7H5ClINO2): 300 [M + H]+, 298
[M + H]+.
[(R)-2-(6-Chloro-5-iodopyridin-3-yloxy)-1-
methylethyl]methylcarbamic Acid tert-Butyl Ester 11
To a solution of compound 10 (525 mg, 1.3 mmol, MW
412.65) in 12 mL of DMF at 0◦C under argon was added CH3I
(0.63 mL, 10.1 mmol, 8 equiv., MW 141.94, d 2.28) followed by
NaH (95%, 61 mg, 2.5 mmol, 2 equiv., MW 24.00). The reac-
tion mixture was stirred overnight at room temperature. After
careful addition of water, the mixture was extracted three times
with Et2O. The organic layers were collected, dried over anhy-
drous MgSO4, and concentrated to dryness. The crude oil was
chromatographed on silica gel using heptane/EtOAc (9/1 to 7/3)
to afford 511 mg (94%) of [(R)-2-(6-chloro-5-iodopyridin-3-
yloxy)-1-methylethyl]methylcarbamic acid tert-butyl ester 11 as
a yellow oil. RF 0.63 (heptane/EtOAc, 1/1 (v/v)). δH (CD2Cl2,
298 K) 8.02 (d, J 3.0, 1H), 7.70 (d, J 2.4, 1H), 4.05–3.80 (m,
3H), 2.75 (s, 3H), 1.42 (s, 9H), 1.21 (d, J 7.3, 3H). δC (CD2Cl2,
298 K) 155.8 (C), 154.1 (C), 145.8 (C), 136.8 (CH), 134.6 (CH),
94.2 (C), 79.8 (C), 70.8 (CH2), 49.8 (CH), 29.5 (CH3), 28.5 (3 ×
CH3), 14.5 (CH3). m/z (C14H20ClIN2O3): 429 [M + H+], 427
[M + H]+.
2-Chloro-5-hydroxy-3-iodopyridine 7
Compound 6 (505 mg, 1.7 mmol, MW 297.48) was dissolved
in aq. 2 N KOH (2.55 mL, 3 equiv.) at 5◦C. After 24 h at room
temperature, the unreacted starting material was removed by fil-
tration. The solution was made acidic (pH 5) by addition of
glacial acetic acid and the precipitated 2-chloro-5-hydroxy-3-
iodopyridine 7 was filtered off as a white solid (380 mg, 88%). RF
0.56 (heptane/EtOAc, 1/1 (v/v)). δH ((D6)acetone, 298 K) 7.98
(d, J 1.5, 1H), 7.78 (d, J 1.5, 1H), 7.46 (br s, 1H). δC ((D6)acetone,
298 K) 154.9 (C), 143.6 (C), 138.1 (CH), 136.4 (CH), 95.0 (C).
m/z (C5H3ClINO): 256 [M + H]+, 254 [M + H]+.
{(R)-2-[6-Chloro-5-((E)-2-pyridin-4-ylvinyl)pyridin-3-
yloxy]-1-methylethyl}carbamic Acid tert-Butyl Ester 12
Compound 10 (1.65 g, 4.0 mmol, MW 412.65) was dis-
solved in 50 mL of acetonitrile. The solution was blanketed
with argon. 4-Vinylpyridine (4.8 mL, 44.0 mmol, 11 equiv., MW
105.14, d 0.975), diisopropylamine (7 mL, 40.0 mmol, 10 equiv.,
MW 129.25, d 0.742), Pd(OAc)2 (900 mg, 4.0 mmol, 1 equiv.,
((R)-2-Hydroxy-1-methylethyl)carbamic Acid
tert-Butyl Ester 9
A solution of BH3·THF in THF (1 m, 100 mL, 0.1 mol, 1.9
equiv.) was added dropwise to a solution of Boc-d-Ala-OH 8

[
11C]p-PVP-MEMA as a PET Radioligand
443
MW 224.49), and P(o-tolyl)3 (1.20 g, 4.0 mmol, 1 equiv., MW
304.38) were successively added to the reaction flask, and the
mixture was then stirred for 3 h at 95◦C. The solvent was
evaporated and the resulting oil was chromatographed on sil-
ica gel using heptane/EtOAc (9/1 to 7/3) to afford 708 mg
(45%) of {(R)-2-[6-chloro-5-((E)-2-pyridin-4-yl-vinyl)pyridin-
3-yloxy]-1-methylethyl}carbamic acid tert-butyl ester 12 as a
brown oil. RF 0.16 (heptane/EtOAc, 1/1 (v/v)). δH (CD2Cl2,
298 K) 8.58 (dd, J 4.9 and 1.8, 2H), 8.01 (d, J 3.0, 1H), 7.68
(br d, 1H), 7.55 (d, J 16.5, 1H), 7.41 (dd, J 4.9 and 1.8, 2H),
7.12 (d, J 15.8, 1H), 4.91 (br s, 1H), 4.15–3.95 (m, 3H), 1.43 (s,
9H), 1.28 (d, J 6.7, 3H). δC (CD2Cl2, 298 K) 155.6 (C), 155.0
(C), 150.6 (2 × CH), 143.9 (C), 142.0 (C), 137.5 (CH), 131.4
(C), 131.1 (CH), 127.8 (CH), 121.4 (2 × CH), 120.4 (CH), 79.6
(C), 72.2 (CH2), 45.8 (CH), 28.5 (3 × CH3), 17.7 (CH3). m/z
(C20H24ClN3O3): 392 [M + H]+, 390 [M + H]+.
{(R)-2-[6-Chloro-5-((E)-2-pyridin-4-ylvinyl)pyridin-
3-yloxy]-1-methylethyl}methylamine 1
To compound 13 (107 mg, 0.3 mmol, MW 403.90) in 2 mL
of CH2Cl2 was added 0.4 mL of TFA. The solution was stirred
for 15 min at room temperature and concentrated to dryness.
The residue was redissolved in 20 mL of CH2Cl2 and washed
twice with 1 N aq. NaOH. The organic layer was dried over
anhydrous MgSO4 and concentrated to dryness to give 75 mg
(93%) of {(R)-2-[6-chloro-5-((E)-2-pyridin-4-ylvinyl)pyridin-
3-yloxy]-1-methylethyl}methylamine 1 as a pale yellow solid.
RF 0.2 (CH2Cl2/MeOH, 9/1 (v/v)). tR 7.5–8.0 min (HPLC A).
δH (CD2Cl2, 298 K) 8.56 (dd, J 4.3 and 1.2, 2H), 7.98 (d, J 2.4,
1H), 7.51 (d, J 3.1, 1H), 7.51 (d, J 15.9, 1H), 7.37 (dd, J 4.3 and
1.8, 2H), 7.01 (d, J 16.5, 1H), 4.00–3.80 (m, 2H), 3.05–2.90 (m,
1H), 2.43 (s, 3H), 1.13 (d, J 6.7, 3H). δC (CD2Cl2, 298 K) 155.1
(C), 150.6 (2 × CH), 143.7 (C), 141.8 (C), 137.1 (CH), 131.4
(C), 130.1 (CH), 127.7 (CH), 121.3 (2 × CH), 120.6 (CH), 73.2
(CH2), 54.3 (CH), 34.0 (CH3), 16.9 (CH3). m/z (C16H18ClN3O):
306 [M + H]+, 304 [M + H]+.
{(R)-2-[6-Chloro-5-((E)-2-pyridin-4-ylvinyl)pyridin-
3-yloxy]-1-methylethyl}methylcarbamic Acid
tert-Butyl Ester 13
4.3. Radiochemistry
4.3.1. Preparation of [11C]Methyl Iodide
Compound 11 (235 mg, 0.5 mmol, MW 426.68) was dis-
solved in 7 mL of acetonitrile. The solution was blanketed
with argon. 4-Vinylpyridine (0.65 mL, 6.0 mmol, 11 equiv., MW
105.14, d 0.975), diisopropylamine (1 mL, 5.7 mmol, 10 equiv.,
MW 129.25, d 0.742), Pd(OAc)2 (124 mg, 0.5 mmol, 1 equiv.,
MW 224.49), and P(o-tolyl)3 (168 mg, 0.5 mmol, 1 equiv., MW
304.38) were successively added to the reaction flask. The
mixture was stirred for 3 h at 95◦C. The solvent was then evap-
orated and the resulting oil was chromatographed on silica
gel using heptane/EtOAc (9/1 to 7/3 (v/v)) to afford 107 mg
(48%) of {(R)-2-[6-chloro-5-((E)-2-pyridin-4-ylvinyl)pyridin-
3-yloxy]-1-methylethyl}methylcarbamic acid tert-butyl ester 13
as a yellow oil. RF 0.16 (heptane/EtOAc, 1/1 (v/v)). δH (CD2Cl2,
298 K) 8.57 (dd, J 4.9 and 1.8, 2H), 7.99 (d, J 3.1, 1H), 7.63 (br
s, 1H), 7.53 (d, J 15.9, 1H), 7.40 (dd, J 4.8 and 1.8, 2H), 7.10
(br s, 1H), 4.15–3.90 (m, 3H), 2.78 (s, 3H), 1.44 (s, 9H), 1.23
(d, J 7.3, 3H). δC (CD2Cl2, 298 K) 155.9 (C), 154.8 (C), 150.5
(2 × CH), 143.8 (C), 141.9 (C), 137.6 (CH), 131.4 (C), 131.1
(CH), 127.7 (CH), 121.3 (2 × CH), 120.6 (CH), 79.6 (C), 70.5
(CH2), 49.4 (CH), 29.9 (CH3), 28.5 (3 × CH3), 14.5 (CH3). m/z
(C21H26ClN3O3): 406 [M + H]+, 404 [M + H]+.
The target gas (N2 + 0.5% O2) was bombarded with protons
using a 16 MeV cyclotron to produce [11C]CO2. The [11C]CO2
was transferred to an automated module and concentrated onto
molecular sieves. The sieves were heated to release [11C]CO2,
which was reduced by hydrogen on a nickel catalyst to form
[11C]CH4. The [11C]CH4 was released into the CH3I conversion
part of the module where it was recirculated through a quartz
column (packed with ascarite and iodine crystals) by helium
carrier gas. The [11C]CH3I formed was trapped in ascarite while
any unconverted [11C]CH4 was transferred to waste.
4.3.2. Preparation and Formulation of
[
11C]p-PVP-MEMA ([11C]-1)
Under helium gas flow, the synthesized [11C]CH3I was
delivered to a 1 mL reaction vessel containing 14 (0.9 mg,
0.003 mmol) in DMF (250 µL) and tetrabutylammonium
hydroxide (2 µL) and allowed to stand at room temperature
for 2 min, followed by heating at 80◦C for 5 min. The reaction
mixture was diluted with 0.5 mL of HPLC buffer and purified
(HPLC B).The radioactive fraction that corresponded to [11C]-1
(tR: 8.6 min) was collected and evaporated under vacuum. The
residuewasreconstitutedinsterilewaterforinjectionsBP(4 mL)
and filtered through a sterile Millipore GS 0.22 µm filter into a
sterile pyrogen-free evacuated vial.
(R)-2-[6-Chloro-5-((E)-2-pyridin-4-ylvinyl)pyridin-
3-yloxy]-1-methylethylamine 14
To compound 12 (444 mg, 1.1 mmol, MW 389.88) in 5 mL
of CH2Cl2 was added 1 mL of TFA. The solution was stirred
for 15 min at room temperature and concentrated to dryness.
The residue was redissolved in 20 mL of CH2Cl2 and washed
twice with 1 N aq. NaOH.The organic layer was dried over anhy-
drous MgSO4 and concentrated to dryness to give 325 mg (98%)
of (R)-2-[6-chloro-5-((E)-2-pyridin-4-ylvinyl)pyridin-3-yloxy]-
1-methylethylamine14asabrownsolid. RF 0.2(CH2Cl2/MeOH,
9/1 (v/v)). δH (CD2Cl2, 298 K) 8.57 (dd, J 4.3 and 1.8, 2H), 8.00
(d, J 3.1, 1H), 7.53 (d, J 16.4, 1H), 7.52 (d, J 3.0, 1H), 7.39 (dd,
J 4.3 and 1.2, 2H), 7.03 (d, J 15.9, 1H), 3.92 (dd, J 8.5 and 4.3,
1H), 3.77 (t, J 8.5, 1H), 3.34 (m, 1H), 1.86 (br s, 2H), 1.16 (d, J
6.7, 3H). δH (CD2Cl2, 298 K) 155.1 (C), 150.6 (2 × CH), 143.8
(C), 141.9 (C), 137.1 (CH), 131.4 (C), 130.9 (CH), 127.8 (CH),
121.4 (2 × CH), 120.6 (CH), 75.6 (CH2), 46.5 (CH), 19.7 (CH3).
m/z C15H16ClN3O: 292 [M + H]+, 290 [M + H]+.
4.3.3. Quality Control of [11C]p-PVP-MEMA ([11C]-1)
For determination of specific radioactivity and radiochemi-
cal purity, an aliquot of the final radioactive solution and was
injected onto an analytical reverse-phase HPLC column (HPLC
C, tR 2.9 min). The area of the UV absorbance peak measured
at 254 nm, which corresponded to the carrier product, was mea-
sured (integrated) on the HPLC chromatogram and compared
with a standard curve relating mass to UV absorbance. The
radioactivity of the collected product was measured and divided
by the found mass to give the specific radioactivity.
4.4. PET Studies
4.4.1. Animal
A male Papio hamadryas baboon aged 13 years and weigh-
ing 26.5 kg was selected for PET scanning. The baboon was

444
F. Dollé et al.
maintained and handled in accordance with the NHMRC code
of practice for the care and use of non-human primates for sci-
entific purposes. The project application was approved by the
Sydney South West Area Health Service (SSWAHS) Animal
Ethics Committee. The radioligand injected dose was 100 MBq.
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4.4.2. Baboon PET Imaging
All PET data were acquired using a Siemens Biograph
LSO PET-CT scanner in the Department of PET and Nuclear
Medicine at Royal Prince Alfred Hospital. This dual modal-
ity device has a fully three-dimensional (3D) PET scanner
with 24 crystal rings and a dual slice CT scanner in the same
gantry. It yields a reconstructed PET spatial resolution of 6.3 mm
FWHM (full width at half maximum) at the centre of the field
of view. A CT scan of the head was completed before radi-
oligand injection. The baboon was initially anaesthetized with
ketamine (8 mg kg−1, im). Anaesthesia was maintained with the
use of an intravenous infusion of ketamine (Parnell Labora-
tory, Australia) in saline at a dose rate of 0.2 mg of ketamine
kg−1 min−1. The baboon also received MgSO4 (2 mL intra-
venous injection of a 2.47 g per 5 mL solution) given over half
an hour plus atropine (1 mg im) plus maxalon (5 mg im). The
head of the baboon was immobilized with plastic tape to mini-
mize motion artefacts. Acquisition of the PET data in list mode
was commenced just before radioligand injection and contin-
ued for a period of 60 min. At the conclusion of the study the
list mode data were sorted into a dynamic scan comprising 54
frames (20 × 30 s, 30 × 60 s, and 4 × 300 s). The dynamic 3D
PET sinograms were rebinned using FORE (Fourier rebinning)
and reconstructed with filtered backprojection and CT databased
corrections for photon attenuation and scatter into 47 transaxial
slices, each comprising 128 × 128 voxels. Reconstructed voxel
dimensions were 0.206 × 0.206 × 0.337 cm3. The radioligand
uptake was converted into units of percent injected dose per
volume of 100 mL of brain tissue (% I.D./100 mL) and plotted
againsttime.Anautomated3Dregistrationalgorithmwasusedto
co-register the two reconstructed scans before region of interest
(ROI) definition. Decay corrected time activity curves repre-
senting the variation in ligand concentration versus time were
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thalamus and cerebellum.
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Acknowledgements
The authors thank Dr Dirk Roeda for proofreading the manuscript. This
work was supported by DEST and the French Embassy in Australia under
the FAST program (FR040051).
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