Synthesis and bioevaluation of [18F]4-fluoro-m- hydroxyphenethylguanidine ([18F]4F-MHPG): A novel radiotracer for quantitative PET studies of cardiac sympathetic innervation

Article abstract of DOI:10.1016/j.bmcl.2013.01.106

A new cardiac sympathetic nerve imaging agent, [¹⁸F]4-fluoro-m- hydroxyphenethylguanidine ([¹⁸F]4F-MHPG), was synthesized and evaluated. The radiosynthetic intermediate [¹⁸F]4-fluoro-m-tyramine ([¹⁸F]4F-MTA) was prepared and then sequentially reacted with cyanogen bromide and NH₄Br/NH₄OH to afford [ ¹⁸F]4F-MHPG. Initial bioevaluations of [¹⁸F]4F-MHPG (biodistribution studies in rats and kinetic studies in the isolated rat heart) were similar to results previously reported for the carbon-11 labeled analog [¹¹C]4F-MHPG. The neuronal uptake rate of [¹⁸F]4F-MHPG into the isolated rat heart was 0.68 ml/min/g wet and its retention time in sympathetic neurons was very long (T_1/2 >13 h). A PET imaging study in a nonhuman primate with [¹⁸F]4F-MHPG provided high quality images of the heart, with heart-to-blood ratios at 80-90 min after injection of 5-to-1. These initial kinetic and imaging studies of [¹⁸F]4F-MHPG suggest that this radiotracer may allow for more accurate quantification of regional cardiac sympathetic nerve density than is currently possible with existing neuronal imaging agents.

Full text of DOI:10.1016/j.bmcl.2013.01.106

Bioorganic & Medicinal Chemistry Letters 23 (2013) 1612–1616
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and bioevaluation of [18F]4-fluoro-m-hydroxyphenethyl-
guanidine ([18F]4F-MHPG): A novel radiotracer for quantitative PET
studies of cardiac sympathetic innervation
⇑
Keun Sam Jang, Yong-Woon Jung, Phillip S. Sherman, Carole A. Quesada, Guie Gu, David M. Raffel
Division of Nuclear Medicine, Department of Radiology, 2276 Medical Science I Building, 1301 Catherine Street, University of Michigan Medical School, Ann Arbor, MI 48109,
United States
a r t i c l e i n f o
a b s t r a c t
A new cardiac sympathetic nerve imaging agent, [18F]4-fluoro-m-hydroxyphenethylguanidine ([18F]4F-
MHPG), was synthesized and evaluated. The radiosynthetic intermediate [18F]4-fluoro-m-tyramine
([18F]4F-MTA) was prepared and then sequentially reacted with cyanogen bromide and NH4Br/NH4OH
to afford [18F]4F-MHPG. Initial bioevaluations of [18F]4F-MHPG (biodistribution studies in rats and kinetic
studies in the isolated rat heart) were similar to results previously reported for the carbon-11 labeled
analog [11C]4F-MHPG. The neuronal uptake rate of [18F]4F-MHPG into the isolated rat heart was
0.68 ml/min/g wet and its retention time in sympathetic neurons was very long (T1/2 >13 h). A PET imag-
ing study in a nonhuman primate with [18F]4F-MHPG provided high quality images of the heart, with
heart-to-blood ratios at 80–90 min after injection of 5-to-1. These initial kinetic and imaging studies of
Article history:
Received 22 October 2012
Revised 17 January 2013
Accepted 22 January 2013
Available online 30 January 2013
Keywords:
Sympathetic nervous system
Metaiodobenzylguanidine
Hydroxyephedrine
[
18F]4F-MHPG suggest that this radiotracer may allow for more accurate quantification of regional car-
Norepinephrine transporter
diac sympathetic nerve density than is currently possible with existing neuronal imaging agents.
Ó 2013 Elsevier Ltd. All rights reserved.
Radioiodinated m-iodobenzylguanidine (MIBG, Fig. 1) was one
of the first radiopharmaceuticals developed for scintigraphic imag-
ing of presynaptic sympathetic nerve fibers in the human heart.1
Clinical studies with MIBG have demonstrated significant changes
in the regional distribution of cardiac sympathetic nerves in many
diseases, including congestive heart failure, diabetic autonomic
neuropathy, myocardial infarction, cardiac arrhythmias, sudden
cardiac death and Parkinson’s disesase.2 Several radiotracers for
noninvasive imaging of cardiac sympathetic innervation with pos-
itron emission tomography (PET) have also been developed,
in high quality images of the heart, this also causes problems in
extracting accurate quantitative measures of regional sympathetic
nerve density from the myocardial kinetics of these agents. NET
transport of these tracers is a fast process and because of this their
neuronal uptake rates are rate-limited by delivery from plasma to
the extracellular spaces near the neurons. Extraction of these trac-
ers from plasma is governed primarily by blood flow, so radiotra-
cers with these kinetic properties are often called ‘flow-limited
tracers’. Since NET transport is not the rate-limiting step in the up-
take of the tracer, it is not possible to extract an estimate of NET
transport rate of the tracer from its myocardial kinetics, as mea-
sured from the acquired PET scan data. This is unfortunate, since
a regional estimate of the NET transport rate of the tracer would
likely serve as a sensitive measure of the regional density of pre-
synaptic nerve terminals. The inability to apply tracer kinetic anal-
ysis approaches forces us to rely instead on semi-quantitative
measures of tracer retention, such as the heart-to-medistinum ra-
tio (HMR) for MIBG and the retention index (RI) for [11C]HED.10
While these have been found to be useful, another consequence
of the rapid neuronal uptake rate of these compounds is that
measures of tracer retention tend to be insensitive to regional
nerve losses until those losses become fairly severe. Thus current
tracers likely do not detect early denervation—which may be
important in providing therapies designed to halt further cardiac
denervation.
including
[
11C]-(ꢀ)-m-hydroxyephedrine ([11C]HED, Fig. 1),3
[
11C]-(ꢀ)-epinephrine ([11C]EPI, Fig. 1),4
[
11C]-(ꢀ)-phenylephrine,5
6-[18F]fluorometaraminol ([18F]6-FMR Fig. 1),6 6-[18F]fluorodop-
amine,7 m-[76Br]bromobenzylguanidine8 and p-[18F]fluorobenzyl-
guanidine ([18F]PFBG).9
All of these tracers are structural analogs of the neurotransmit-
ter norepinephrine. They are initially transported into cardiac sym-
pathetic neurons as substrates of the norepinephrine transporter
(NET). Once inside the neurons, to varying degrees these com-
pounds are taken up into norepinephrine storage vesicles by the
second isoform of the vesicular monoamine transporter
(VMAT2).10 While the rapid neuronal uptake of these agents results
⇑
Corresponding author. Tel.: +1 (734) 936 0725; fax: +1 (734) 764 0288.
E-mail address: raffel@umich.edu (D.M. Raffel).
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.01.106

K. S. Jang et al. / Bioorg. Med. Chem. Lett. 23 (2013) 1612–1616
1613
Figure 1. Structures of cardiac sympathetic nerve imaging agents.
The only way to overcome these obstacles to accurate and sen-
sitive detection of cardiac denervation is to develop a new tracer
that possesses optimal kinetics for tracer kinetic analyses. Such
tracers would provide more accurate and sensitive measures of re-
gional nerve density, allowing detection of denervation earlier in
the course of diseases that cause nerve damage, such as diabetic
autonomic neuropathy and heart failure. We hypothesized that a
new radiolabeled NET substrate should possess two kinetic proper-
ties to be better suited for tracer kinetic analyses: (1) a slower neu-
ronal uptake rate; and (2) a very long neuronal retention time,
through efficient vesicular storage. We believed that compounds
with these kinetic properties could be found among the various
guanidine derivatives that show potent pharmacological effects
on cardiac sympathetic neurons. In particular, we chose to study
phenethylguanidines because some of these compounds are
known to be potent depletors of cardiac norepinephrine stores
in vivo, due to their avid uptake and retention inside norepineph-
rine storage vesicles.11
Evaluations of a series of carbon-11 labeled phenethylguani-
dines have previously been reported.12 Among the compounds
tested, [11C]-4-fluoro-m-hydroxy-phenethylguanidine ([11C]4F-MHPG,
Fig. 1) was found to possess the desired kinetic properties of a
slower NET transport rate and a very long neuronal retention time.
Also, microPET studies in rhesus macaque monkeys demonstrated
that this agent had favorable in vivo imaging properties and
kinetics. These encouraging results led us to attempt the synthesis
of fluorine-18 labeled 4-fluoro-m-hydroxy-phenethylguanidine
([18F]4F-MHPG). While the short half-life of carbon-11 (20.1 min)
limits its wide spread application due to the requirement of an
on-site cyclotron, the longer half-life of fluorine-18 (109.8 min)
allows for imaging studies at imaging centers without a cyclotron
through distribution by commercial vendors. The longer half-life of
fluorine-18 also allows for imaging times up to several hours after
injection into a patient and permits multiple patients doses to be
dispensed from a single synthesis batch.
We describe here the preparation of a new fluorine-18 radio-
tracer ([18F]4F-MHPG) for imaging cardiac sympathetic innerva-
tion with PET and the results of initial bioevaluation studies in
rats and a non-human primate. Biological data for [18F]4F-MHPG
are compared to previous results obtained with [11C]4F-MHPG.
Reference standards for HPLC and in vitro studies, 4F-MHPG 1
and 4-fluoro-m-tyramine (4F-MTA, 7), were prepared from the
starting material 3-benzyloxy-4-fluorobenzaldehyde 2 (Scheme 1).
The benzaldehyde 2 was reduced with NaBH4 to afford the benzyl
alcohol 3. The alcohol 3 was converted to the benzyl bromide 4 by
reaction with PBr3 and then followed by treatment with sodium
cyanide in DMSO to generate the benzyl cyanide 5. Reduction of
cyano group with borane and deprotection of the benzyl
group with 48% HBr was carried out to provide 4F-MTA 7. Conden-
sation of 4F-MTA with 1,3-bis(tert-butoxycarbonyl)-2-methyl-2-
thiopseudourea13 and then followed by deprotection under mild
acidic condition afforded 4F-MHPG 1. Another reference standard,
Scheme 1. Reagents and conditions: (a) NaBH4, THF, 0 °C to rt, N2, 4 h, 72%; (b) PBr3, CH2Cl2, rt, overnight, 37%; (c) NaCN, DMSO, rt, 3 h, 90%; (d) 1.0 M BH3/THF complex, THF,
reflux, 2 h, 69%; (e) HBr (48%), 130 °C, N2, 6 h, 97%; (f) 1,3-bis(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea, HgCl2, Et3N, DMF, 0 °C to rt, 24 h, 87%, (g) 1.0 N HCl, CH2Cl2/
MeOH, rt, 24 h, 87%.

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K. S. Jang et al. / Bioorg. Med. Chem. Lett. 23 (2013) 1612–1616
Scheme 2. Reagents and conditions: (a) dimethylamine hydrochloride, K2CO3, DMSO/H2O (2.5:1), 110 °C, overnight, 82%; (b) CH3OTf, CH2Cl2, N2, rt, overnight, 71%; (c)
18F]Fꢀ-Kryptofix-2.2.2; (d) CH3NO2, NH4OAc, MeOH/AcOH; (e) BH3/LAH; (f) 48% HBr; (g) CNBr (5.0 M in CH3CN);(h) NH4Br/NH4OH.
[
3-benzyloxy-4-fluoro-b-nitrostyrene 12, was prepared by the con-
densation of 3-benzyloxy-4-fluorobenzaldehyde 2 with nitrometh-
ane in the presence of ammonium acetate and glacial acetic acid
(Scheme 2).14 The precursor for labeling of [18F]4F-MHPG, 3-ben-
zyloxy-4-formyl-N,N,N-trimethylanilinium trifluoromethanesulfo-
nate 10, was synthesized according to the previously published
method.15 3-Benzyloxy-4-fluorobenzaldehyde 2 was converted to
the dimethylamine 9 in 82% yield by the nucleophilic substitution
reaction of fluorine with Me2NH. The quarternary salt 10 was ob-
tained in 71% yield by the treatment of 9 with methyl trifluoro-
methanesulfonate at room temperature under nitrogen.
ever, this reaction led to the formation of several radioactive impu-
rities with low radiochemical yield. Use of other reagents such
as cyanamide18 N,N0-bis(t-butyloxycarbonyl)thiourea19,20 and
1-guanyl-3,5-dimethylpyrazole21 were not successful. Although
one of the most efficient methods reported in the literature seems
to be treatment of N,N0-bis(t-butyloxycarbonyl)thiourea with mer-
curic chloride,22 this reaction is not practical for a radiotracer that
will be injected into non-human primates or humans due to the
toxicity of mercuric sulfide produced as a side product. These
initial findings led us to attempt a two-step reaction, first with
cyanogen bromide, followed by treatment with NH4Br/NH4OH.
This approach was adapted from our previous synthesis of
Synthesis of the target compound [18F]4F-MHPG is shown in
Scheme 2. This approach is based on previously established meth-
ods adapted from syntheses of [11C]tyramine16 and 6-[18F]fluoro-
[
11C]4F-MHPG.12 Purified [18F]4F-MTA was reacted with cyanogen
bromide for 3 min at 120 °C and subsequently treated with NH4Br/
NH4OH for 15 min at 130 °C, followed by HPLC purification to af-
ford the final product [18F]4F-MHPG. The structure of the purified
product was verified by comparing its retention time against co-in-
jected non-radioactive standard of 4F-MHPG using reverse-phase
dopamine.17 The synthesis of
[
18F]4F-MHPG was started by
production of [18F]benzaldehyde 11 through a no-carrier-added
nucleophilic aromatic substitution reaction with K[18F]F-K2.2.2 with
the precursor 3-benzyloxy-4-formyl-N,N,N-trimethylanilinium tri-
flate 10. The trimethylanilinium group in benzaldehyde afforded
high incorporation of [18F]fluoride in the nucleophilic aromatic
substitution reaction, providing a good radiochemical yield.15 In
the second step, 4-[18F]fluoro-3-benzyloxybenzaldehyde 11 was
condensed in situ with nitromethane in the presence of ammo-
nium acetate/acetic acid/methanol to provide [18F]nitrostyrene
12. The above two-step reaction was performed in a GE TRACERlab
FX-N radiosynthesis module (GE HealthCare, Waukesha, WI, USA),
with 15 4% radiochemical yield and >98% radiochemical purity.
The next step simultaneously reduced both the alkene group and
nitro group of [18F]nitrostyrene. When lithium aluminum hydride
(LAH) was used for this step, the reduction of both groups in 12
was not efficient. However, the sequential addition of borane fol-
lowed by LAH increased the radiochemical yield. Cleavage of the
benzyl ether protecting group with 48% HBr followed by HPLC
purification afforded the intermediate 4-[18F]-fluoro-m-tyramine
([18F]4F-MTA; 7). The structure of the purified product was verified
by comparing its retention time against a non-radioactive standard
of 4F-MTA that was co-injected onto a reverse-phase HPLC column
HPLC (Synergi Hydro 4
l
, 250 ꢁ 4.6 mm, 10% EtOH in 60 mM NaH2-
PO4, 1.1 ml/min, Rt = 10.4 min). The total synthesis time from pro-
duction of [18F]fluoride ion to obtaining the final product was 200–
220 min. The overall decay-corrected radiochemical yield was 1–
2% with >98% radiochemical purity. The specific activity of
[
18F]4F-MHPG was 0.3–0.5 Ci/
lmol at the end of synthesis. The
radiolabeling steps were not optimized for radiochemical yields
and reaction times. Radiochemistry would need to be further im-
proved to optimize production for clinical use of this radiotracer.
Kinetic studies in isolated rat heart
Uptake rates of [18F]4F-MHPG into sympathetic neurons, as well
as the ability of cardiac neurons to retain these compounds, were
assessed by performing kinetic studies in an isolated working rat
heart preparation, using previously reported methods.12 In these
studies the extraneuronal catecholamine uptake mechanism in
the rat heart (‘uptake-2’) was inhibited by adding 54 lM cortico-
sterone to the heart perfusion buffer.23 Neuronal uptake rates
(Kup; ml/min/g wet) were measured by performing a 10 min infu-
sion of the radiotracer at a constant perfusate concentration into
the isolated heart. At the end of the constant infusion period, the
heart was switched to normal perfusion buffer for 120 min to
measure radiotracer clearance rates (expressed as a clearance
(Synergi Hydro 4
l
, 250 ꢁ 4.6 mm, 5% EtOH in 60 mM NaH2PO4,
1.2 ml/min, Rt = 10.8 min). In the final step, conversion of the pri-
mary amine of [18F]4F-MTA to a guanidine to form [18F]4F-MHPG
was initially attempted by reacting the purified [18F]4F-MTA with
2-methyl-2-thiopseudourea sulfate, as previously reported.9 How-

K. S. Jang et al. / Bioorg. Med. Chem. Lett. 23 (2013) 1612–1616
1615
statistically significant differences in the uptake of the two tracers
in any organ. For comparison, biodistribution data for [125I]MIBG1
and [11C]HED12 are also provided in Table 2. The 4F-MHPG deriva-
tives had lower uptake into left ventricle consistent with their NET
transport rates being slower than those of MIBG and HED.
MicroPET imaging studies in rhesus macaque
The hearts of monkeys27 and humans28,29 lack the extraneuro-
nal uptake (uptake-2) pathway of catecholamines, making the
monkey a more appropriate animal model for evaluating sympa-
thetic nerve tracers than the dog, which has significant uptake-2
activity.30 PET imaging with [18F]4F-MHPG was performed in a
rhesus macaque monkey to assess its in vivo imaging properties.
Cardiac uptake of [18F]4F-MHPG provided high quality images,
with uniform uptake in the left ventricle and final heart-to-blood
activity ratios (80–90 min after injection) were 5-to-1. There was
essentially no retention of the tracer in the lungs. Uptake of
Figure 2. Kinetics of [11C]4F-MHPG and [18F]4F-MHPG in the isolated rat heart. A
10-min constant infusion study assesses the neuronal uptake rate of the tracer into
sympathetic nerve terminals, after which the heart is switched back to normal heart
perfusate to study clearance rates. Both tracers exhibit very long neuronal retention
times due to sequestration inside norepinephrine storage vesicles.
[
18F]4F-MHPG in the liver was a little lower than the cardiac up-
take, unlike the relatively high liver uptake seen previously with
other sympathetic nerve radiotracers such as MIBG and [11C]HED,
resulting in improved overall image quality. There was little or
no activity observed in the vertebrae of the spine in sagittal
images, suggesting there is little in vivo defluorination of the com-
pound. Further work is needed to characterize the kinetics and
in vivo metabolism of [18F]4F-MHPG.
half-time, T1/2, in h). The kinetics of [18F]4F-MHPG in the isolated
rat heart were very similar to those of [11C]4F-MHPG (Fig. 2). The
neuronal uptake rate of [18F]4F-MHPG in the isolated rat heart
was Kup = 0.68 ml/min/g wet and neuronal retention times were
very long (clearance T1/2 >13 h). These values are very similar to
those previously observed for [11C]4F-MHPG (Kup = 0.72 ml/min/g
wet; T1/2 >73 h).12 For comparison, these values, along with Kup
In conclusion, [18F]4F-MHPG was successfully prepared and ini-
tial biological studies demonstrated its kinetic properties were
consistent with those we targeted as being optimal for tracer ki-
netic analyses in human PET studies of cardiac sympathetic inner-
vation. MicroPET imaging studies in a monkey provided high
quality images of the regional distribution of sympathetic nerves
in the heart. These positive initial results demonstrate that
and T1/2 values for [123I]MIBG,24 11C]HED25 and [18F]PFBG,26 are
[
shown in Table 1. The slower neuronal uptake rate and very long
retention kinetics of [18F]4F-MHPG are consistent with those we
targeted as being ideal for tracer kinetic analyses in human PET
studies of cardiac sympathetic innervation.12
[
18F]4F-MHPG is a promising candidate for further development
Biodistribution studies in rats
as a radiotracer for clinical PET studies of cardiac sympathetic
innervation.
The biodistribution of [18F]4F-MHPG into various tissues of the
rat at t = 30 min after intravenous injection was determined. Bio-
distribution data for [18F]4F-MHPG were very similar to results
previously obtained with [11C]4F-MHPG (Table 2). The 18F-labeled
analog exhibited somewhat lower uptake into heart and lung,
Acknowledgments
We thank the staff of the University of Michigan Cyclotron/PET
Facility for their support in the preparation and evaluation of all
radiopharmaceuticals included in this work. This work was sup-
ported by Grant R01-HL079540 from the National Heart Lung
and Blood Institute, National Institutes of Health, Bethesda MD
USA.
while distribution of
[
18F]4F-MHPG into other adrenergically
innervated tissues like the spleen and adrenal medulla were very
consistent with the results seen with [11C]4F-MHPG. A two-tailed
t-test, assuming unequal variances, demonstrated there were no
Table 1
Neuronal uptake rates (Kup) and major clearance half-times (T1/2) in isolated rat heartsa
Tracer
Acronym
Kup (ml/min/g wet)
Major clearance T1/2 (h)
Ref.
[
[
123I]-m-iodobenzylguanidine
11C]-(ꢀ)-m-hydroxyephedrine
[
[
[
[
[
123I]MIBG
3.6 0.2
2.7 0.4
1.2 0.4
0.72
3.5 1.8
1.1 0.3
0.53 0.06
>73
24
25
26
12
11C]HED
p-[18F]fluorobenzylguanidine
18F]PFBG
[
[
11C]4-fluoro-m-hydroxyphenethylguanidine
18F]4-fluoro-m-hydroxyphenethylguanidine
11C]4F-MHPG
18F]4F-MHPG
0.68
>13
This work
a
Extraneuronal uptake (uptake-2) was blocked pharmacologically.
Table 2
Tissue concentrations at t = 30 min in rats (% injected dose/g, n = 5 each)
Tracer
Left ventricle
Lung
Liver
Spleen
Adrenal medulla
Blood
Ref.
[
[
[
[
125I]MIBG
3.63 0.20
2.85 0.42
1.77 0.27
1.45 0.13
2.31 0.19
0.40 0.12
0.56 0.15
0.43 0.08
1.19 0.06
2.32 0.25
1.22 0.18
1.14 0.16
0.85 0.06
1.31 0.14
0.52 0.10
0.56 0.10
1.53 0.08
0.72 0.08
0.56 0.21
0.54 0.08
0.10 0.01
0.08 0.01
0.08 0.01
0.07 0.01
1
12
12
This work
11C]HED
11C]4F-MHPG
18F]4F-MHPG
Values are mean SD.

1616
K. S. Jang et al. / Bioorg. Med. Chem. Lett. 23 (2013) 1612–1616
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