Synthesis and cardiac imaging of 18F-ligands selective for β1-adrenoreceptors

Article abstract of DOI:10.1021/ml1002458

A series of potent and selective β₁-adrenoreceptor ligands were identified (IC₅₀ range, 0.04-0.25 nM; β₁/ β₂ selectivity range, 65-450-fold), labeled with the PET radioisotope fluorine-18 and evaluated in normal Sprague-Dawley rats. Tissue distribution studies demonstrated uptake of each radiotracers from the blood pool into the myocardium (0.48-0.62% ID/g), lung (0.63-0.97% ID/g), and liver (1.03-1.14% ID/g). Dynamic μPET imaging confirmed the in vivo dissection studies.

Full text of DOI:10.1021/ml1002458

LETTER
pubs.acs.org/acsmedchemlett
Synthesis and Cardiac Imaging of 18F-Ligands Selective for
β1-Adrenoreceptors
Heike S. Radeke,* Ajay Purohit, Thomas D. Harris, Kelley Hanson, Reinaldo Jones, Carol Hu,
Padmaja Yalamanchili, Megan Hayes, Ming Yu, Mary Guaraldi, Mikhail Kagan, Michael Azure,
Michael Cdebaca, Simon Robinson, and David Casebier
Research and Development, Lantheus Medical Imaging, 331 Treble Cove Road, North Billerica, Massachusetts 01862, United States
S Supporting Information
b
ABSTRACT: A series of potent and selective β1-adrenoreceptor ligands were identified
(IC50 range, 0.04ꢀ0.25 nM; β1/β2 selectivity range, 65ꢀ450-fold), labeled with the PET
radioisotope fluorine-18 and evaluated in normal SpragueꢀDawley rats. Tissue distribu-
tion studies demonstrated uptake of each radiotracers from the blood pool into the
myocardium (0.48ꢀ0.62% ID/g), lung (0.63ꢀ0.97% ID/g), and liver (1.03ꢀ1.14% ID/g). Dynamic μPET imaging confirmed the
in vivo dissection studies.
KEYWORDS: PET, β1-selective ligand, cardiac imaging, heart failure, 18F-labeling
he β1- and β2-adrenoreceptors (β-AR) play an important
role in the regulation of heart function and have been
demonstrated capacity for visualization and quantification of β-
AR density alone rather than the β1-AR population specifically is
less valuable for assessment of cardiac diseases.15
T
extensively studied in recent decades,1,2 as changes in the number
and ratio of cardiac β-ARs have been associated with several
diseases of the heart including myocardial ischemia,3 congestive
heart failure,4 cardiomyopathy,5 and hypertention.6 In the healthy
human heart, β1-AR is the dominant subtype (4:1 ratio, β1:β2-AR)
and widely distributed. However, in the failing heart, a predictable
decrease in cardiac β1-AR density (3:2 ratio, β1:β2-AR density
observed in heart tissue of postmortem heart failure patients),
coupled with enhanced sympathetic activity, boosting cardiac-
derived noradrenaline and adrenaline levels, leads to further
desensitization and subsequent down-regulation of β1-ARs as well
as a decrease in cardiac contractility, the hallmark of heart failure.7
In addition, it has been shown that β1-AR down-regulation
precedes clinical heart failure and may indeed be an early clinical
marker of left ventricular dysfunction.8
In contrast, the β1-AR selective antagonist ICI 89,406 (1;
Scheme 1) has previously been shown to produce effective
blockage of β1-AR during exercise in patients with angina
pectoris.16 As such, Schaefer et al. chose this compound as their
lead structure in the development of new β1-AR selective ligands
for PET and SPECT.17ꢀ19 Notably, the authors developed an O-
methyl derivative of 1, labeled with carbon-11 ([11C]OMe-ICI
89,406; [11C]2), that exhibited high affinity and selectivity for β1-
AR in vitro. Unfortunately, in vivo studies did not demonstrate
high specific binding to myocardial β1-AR; rapid metabolism and
high nonspecific binding in the myocardium were observed.20
Our goal in the present study was to expand on the known
structureꢀactivity profile of 1 and evaluate multiple 18F-labeled
derivatives through in vivo imaging studies.21,22 Traditionally,
ICI 89,406 along with a very small set of nonfluorinated
derivatives were prepared via the acid-catalyzed epoxide opening
of (S)-(oxiran-2-ylmethoxy)benzonitrile with an appropriately
functionalized amine (Scheme 1).19 The various fluorinated β1-
ligands prepared in our study took advantage of this synthetic
disconnection approach, where several functionalized amines
were first prepared and then exposed to a series of substituted
(S)-(oxiran-2-ylmethoxy)benzonitriles to create a diverse set of
compounds with A and B regions as shown in Chart 1.
To date, the human heart has been extensively studied with
positron emission tomography (PET) and single photon emis-
sion computed tomography (SPECT) to assess myocardial
blood flow and substrate metabolism.9 However, these imaging
techniques have yet to realize the opportunity of noninvasive
assessment of cardiac AR density, distribution, and occupancy
using endogenous ligands or drugs,10 where the capacity of PET
to be used for repeat measurements may significantly aid in
monitoring and treatment of various heart diseases.11 Identifica-
tion of the population at risk for developing heart failure before
clinical symptoms are noticed would greatly improve patient
management as well as the stratification of a patient population
that would benefit from placement of an implantable cardiover-
ter-defibrillator (ICD).12
In conjunction, two complementary synthetic strategies were
developed to generate the requisite functionalized amino-urea
derivatives. Within each analogue, the central urea linkage was
constructed through condensation of tert-butyl-2-aminoethylcar-
bamate with either a commercially available isocyanate or an
At present, however, no optimal radioligands for imaging
cardiac β1-AR using SPECT or PET are available,13 where the
most extensively studied tracer in cardiovascular disease patients
is the nonselective ligand [11C]CGP-12177.14 Regrettably, its
Received: October 11, 2010
Accepted: July 22, 2011
Published: July 22, 2011
r
2011 American Chemical Society
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LETTER
in situ-generated p-nitrophenylcarbamate (Schemes 2 and 3 and
Supporting Information).
In certain cases, additional functional group manipulations
were required to complete the construct prior to reaction with
the substituted (S)-(oxiran-2-ylmethoxy)benzonitriles, while in
others, simple deprotection of the derived urea remained to
generate the requisite coupling partner.23
To generate multiple radioligands more efficiently, the radio-
synthetic procedure that we chose for labeling compounds 5ꢀ7
utilized a well-established, two-step process that allows for
labeling of multiple phenolic precursors with various 18F-labeled
alkyl substituents (Scheme 4).24 A robotic radiosynthesis station,
which can conduct multistep radiosynthetic procedures, was
developed and evaluated with our selected precursor phenols.
For preparation of the conjugate 18F-labeled alkylfluorides,
precursor materials were required that contain activated leaving
groups such as sulfonate esters (e.g., tosylates, mesylate). Pri-
mary derivatives were preferred because of their ease of displace-
ment with fluorine-18 as compared to secondary derivatives,
which often eliminate under the basic fluorination conditions.
With these caveats in mind, we first generated the 18F-labeled
radioligands [18F]fluoroethyl-(41) and [18F]fluoropropyl tosy-
late (62) from their respective bis-tosylate precursors using a
combination of published methods.25 Subsequent reaction of 41
and 62 with phenol precursors 47 or 49 under standard William-
son conditions afforded [18F]5ꢀ7 after high-performance liquid
chromatography (HPLC) purification (11ꢀ31% conversion
after 30 min; see the Supporting Information for details).
Notably, for each radiotracer, ∼25 mCi of the final compound
was isolated from ∼500 mCi of [18F]NaF in high radiochemical
purity; the total synthesis time was 120 min. Specific activity
values ranged from 750 to 2000 mCi/μmol depending upon the
final radioactive concentration. Significantly, the single-step
labeling process, ([18F]KF, K222, MeCN, 90 °C, 15 min), using
the derivative tosylate precursors of [18F]5ꢀ7, demonstrated
rather poor chemical efficiency (<2% radiochemical yield).
Initial synthetic efforts were directed toward introduction of a
fluorine atom into the B region of 1 (Table 1). Importantly, the
aromatic fluorides 3 and 4 both exhibited potent β1-AR binding
activity (IC50 = 0.2 and 0.1 nM, respectively) and β1/β2-AR
selectivity (69- and 150-fold, respectively), revealing a modest
preference for locating fluorine at the para-position of the
Scheme 1. Synthesis of ICI 89, 406, and Analoguesa
a Reagents and conditions: (a) HCl, dioxane, or TFA, CH2Cl2, 55ꢀ98%.
(b) MeCN or i-PrOH, i-Pr2NEt, Et2BOMe, Yb(OTf)3, 43ꢀ45%;
method A, B, or C, 10ꢀ45%.
Chart 1. Diverse Moieties for the A and B Region Linked via the ICI 89,406 Backbone
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LETTER
Scheme 2a
Scheme 4a
a Reagent and conditions: (a) Compound 41 or 62, K2CO3, MeCN,
95 °C, 20 min.
Table 1. Fluorinated Analogues of ICI 89,406 (1) and OMe-
ICI 89,406 (2)
a Reagents and conditions: (a) tert-Butyl-2-aminoethylcarbamate, THF,
0 °C, 2.5ꢀ16 h, 47ꢀ93%. (b) H2, Pd/C, EtOH, 12 h, 91%. (c)
2-Fluoroethanol, diisopropyl azodicarboxylate, PPh3, THF, 5 h, 20%.
(d) 3-Fluoropropyl tosylate, NaOH, DMSO, 75 °C, 30 min, 71%. (e)
Pd/C, H2, MeOH. (f) Fluoroacetone, NaBH(OAc)3, THF.
a
compound
β1
β2/β1
cLogD
A1ꢀB1 (2)
0.11
145
69
0.85
0.57
A1ꢀB2 (3)
0.2
A1ꢀB3 (4)
0.1
150
448
65
1.23
A1ꢀB4 (5)
0.08
0.25
0.04
1.5
1.05
Scheme 3. Synthesis of Carbamates 38, 40, 51ꢀ60, 63, and
65a
A1ꢀB5 (6)
1.42
A1ꢀB6 (7)
265
13
1.03
A1ꢀB7 (8)
0.39
A2ꢀB8 (9)
21
164
70
ꢀ0.53
ꢀ1.87
ꢀ1.66
2.07
A3ꢀB8 (10)
A1ꢀB9 (11)
A2ꢀB10 (12)
A1ꢀB11 (13)
A1ꢀB12 (14)
A1ꢀB13 (15)
A1ꢀB14 (16)
A1ꢀB15 (17)
A1ꢀB16 (18)
A1ꢀB17 (19)
A1ꢀB18 (20)
A1ꢀB19 (21)
A1ꢀB20 (22)
A1ꢀB21 (23)
A1ꢀB22 (24)
A1ꢀB23 (25)
2
1
511
32
2
0.1
0.3
0.05
0.05
0.35
50
0.92
345
723
>1000
163
8
0.19
0.86
0.47
0.35
26
1.04
10
>100
20
10
ꢀ0.13
ꢀ0.59
ꢀ0.74
0.92
0.05
a PG (protecting group) = Boc or Cbz. Reagents and conditions: (a) (i)
4-Nitrophenyl chloroformate, pyridine, solvent, overnight; (ii) NBoc-
ethylenediamine, base, DMF or THF, 15 min ꢀ2 h, 29ꢀ94%. (b) H2,
Pd/C, EtOH, 90ꢀ96%. (c) 2-Fluoroethyl tosylate, K2CO3, DMF,
50ꢀ80 °C, 2ꢀ24 h, 42ꢀ96%.
4
4
10
3
30
6
0.42
0.14
1.28
5
0.1
0.91
a IC50 values are expressed in nanomolar concentrations.
aromatic ring. Alternatively, extension of the methoxy function in
2 to fluoroethoxy derivative 5 resulted in a 3-fold increase in
selectivity while maintaining β1-AR binding potency.26 Interest-
ingly, further extension to yield a fluoropropoxy function (6)
resulted in decreased β1-AR binding potency and subtype
selectivity as compared to 2. Maintaining the fluoroethoxy group
in 5 with transposition to the meta-position did, however,
improve β1-AR potency albeit with reduced selectivity (e.g., 5
and 7, Table 1). Relocating the fluorine atom from the B region
(5) to the A region as in 12 induced a marked decrease in β1-AR
potency and selectivity. Lastly, when the fluoroethoxy group was
replaced with a fluorinated amino derivative, β1-AR potency and
selectivity significantly decreased (8). Taken together, fluorine
substitution was better tolerated on the B ring with regard to
both β1-AR potency and selectivity.
potency to β1-AR (IC50 = 21 and 2 nM, respectively), while
maintaining good β1/β2-AR selectivity (164- and 70-fold, re-
spectively; Table 1). Transposing the fluorine atom from the A
region to the B region (11) once again resulted in a significant
increase in β1-AR binding activity and selectivity as compared to
9 and 10. Although compounds 9ꢀ11 were comparable in their
selectivity profile to 3ꢀ7, the β1-AR binding potency was
approximately 10-fold lower.
Despite numerous reports of β1-AR ligands that contain an
aryloxy propanolamine pharmacophore, many of these com-
pounds are in fact not selective for β1-AR.28 Considering 5ꢀ7
contain both the aryloxy propanolamine backbone and a urea-
substituted aromatic system (B region), one may conclude that
the enhanced β1-AR potency and selectivity is in fact attributed
to these additional structural features. As such, supplemental
structureꢀactivity relationship (SAR) studies were conducted to
evaluate structural requirements within the aryloxy propanola-
mine backbone of ligands 5ꢀ7 necessary to maintain potency
Previous studies have identified potent β1-AR selective ICI
89,406 analogues, which contain a carboxylic acid residue in the
para-position of the B ring.27 Hence, a set of fluorinated
analogues (9ꢀ11), which contain a related substitution pattern,
were prepared. Compounds 9 and 10 exhibit moderate binding
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Table 2. Biodistribution of [18F]-ICI 89,406 Analogues in
Ratsa,b
organ
[
18F]5b
[
18F]6a
[
18F]7b
blood
heart
0.18 ( 0.07
0.48 ( 0.16
0.97 ( 0.26
1.14 ( 0.33
0.37 ( 0.02
1.26 ( 0.29
0.27 ( 0.05
0.08 ( 0.02
0.21 ( 0.01
0.42 ( 0.15
0.63 ( 0.27
1.03 ( 0.52
0.40 ( 15
0.14 ( 0.05
0.62 ( 0.03
0.79 ( 0.11
1.14 ( 0.12
0.52 ( 0.09
2.01 ( 0.21
0.16 ( 0.01
0.10 ( 0.01
lung
liver
spleen
kidney
femur
muscle
1.38 ( 0.16
0.63 ( 0.16
0.09 ( 0.01
a Data are expressed as the % ID/g ( SD with three animals per data
point at 30 min postinjection. b Data are expressed as the % ID/g ( SEM
with two animals per data point at 30 min postinjection.
and selectivity. For example, introduction of a heteroatom in the
B ring of parent structures 4 and 5 afforded the fluorinated
pyridine derivatives 14 and 13, respectively. Notably, 14 exhib-
ited a 3-fold decrease in β1-AR potency and a nearly 2-fold
increase in β1-AR selectivity as compared to 4, while compound
13 maintained β1-AR potency, albeit with markedly decreased
selectivity as compared to 5. Replacement of the fluorine atom in
14 with iodine or bromine yielded compounds 15 and 16, which
exhibited increased β1-AR potency and selectivity; 15 and 16
may prove interesting structural targets as 124I and 76Br-labeled
PET radiotracers.
Figure 1. Images of the rat heart at 30 min. (a) Horizontal long axis, (b)
short axis, and (c) vertical long axis.
Introduction of an additional nitrogen atom in the B ring of 16
generated a fluorinated pyrimidine analogue, which resulted in a
minor decrease in β1-AR potency and selectivity (17; IC50 = 0.35
nM; 163-fold), whereas replacement of the B ring with 5-mem-
bered heterocycles such as thiazole (18) or tetrazole (19) proved
detrimental for both β1-AR potency and selectivity. Not surpris-
ingly, substitution of the B ring with saturated heterocycles as in
20 and 21 markedly decreased potency and selectivity and
confirmed the aromatic structural requirements outlined above.
A small structureꢀactivity profile of the urea functionality within
the linker connecting the A and B regions in 5ꢀ7 was also
generated, where removal of either nitrogen atom within the urea
functionality of 4 and 14 to afford the derived amides 24 and 23,
respectively, resulted in >10-fold decrease in both potency and
selectivity. Replacement of the urea moiety with a sulfonamide
linker (25) also proved detrimental. Overall, no improved
functional groups were identified.
Figure 2. Timeꢀactivity curves from the imaging data of [18F]7.
the heart and the liver. In these cases, uptake of radioligands
[18F]5ꢀ7 appears unaffected by the position or length of the
fluoroalkyl side chain.
Considering low expression of the β1 receptor subtype, the
observed preferential uptake of these tracers in lung tissue is
likely nonspecific in nature. While this detail is consistent with
the published literature,20 several authors report challenges
associated with the in vivo demonstration of subtype selectivity,
including achieving a proper balance of specific activity and
receptor occupancy as well as mediating the pharmacologic
effects of preferred blocking agents (i.e., bradycardia from
metaprolol). Despite achieving appropriate levels of specific
activity in the present study, the observed tissue distribution will
likely complicate future in vivo blocking studies.
Despite low statistical power, the abbreviated in vivo dissec-
tion studies outlined above help to establish gross differences in
compound distribution and facilitate SAR development. More
extensive, statistically relevant studies are however required, to
distinguish subtle distribution differences and finalize lead can-
didate selection.
In summary, compounds 3ꢀ7, 13, and 14, each containing a
fluorine atom, exhibited β1-AR binding (IC50 = 0.04ꢀ0.30 nM)
and good receptor selectivity (50ꢀ450-fold) suitable for imaging
studies. Our criteria for radioligand selection were the following:
(a) β1-binding affinity, <1 nM; (b) β1/β2 selectivity >50; (c)
moderate cLogD values; and (d) readily labeled with fluorine-18.
Compounds 5ꢀ7 were thus selected as representative candidates
for labeling with fluorine-18 as they achieved our selection
criteria, provided a range of activity and selectivity values, and
maintained a cLogD value near one.
Biodistribution studies of [18F]5ꢀ7 in SpragueꢀDawley
(SD) rats are summarized in Table 2. In general, high extraction
of the radiotracers from the blood pool into tissues such as heart,
lung, and liver was observed at 30 min postinjection. Heart
uptake of compounds [18F]5ꢀ7 was 0.48, 0.42, and 0.62% ID/g,
at 30 min, with corresponding heart:lung ratios of 1:2, 1:1.5, and
1:1.27, respectively. Similar values were also observed between
Dynamic PET imaging studies carried out on SD rats sup-
ported the biodistribution results. All three radiotracers were
clearly visualized in both the myocardium and the liver at 30 min
postinjection; however, at 60 min, significant wash-out of all
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LETTER
study. This material is available free of charge via the Internet at
http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*Tel: 978-671-8151. Fax 978-436-7500. E-mail: heike.radeke@
lantheus.com.
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three radiotracers was observed. Importantly, no interference
from uptake in the lung was detected (Figure 1). In vivo
metabolism study of [18F]7 revealed progressive loss of the
parent species over time beginning at 83% and ending at 44%
(2 and 30 min, respectively); a 30 min urine sample contained
76% of the parent species. Two unique metabolites were
observed by HPLC analysis.
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compound [18F]7 was chosen as a representative example for
more detailed in vivo evaluation. Timeꢀactivity plots generated
through further study of [18F]7 showed rapid uptake of the
radiotracer from the blood pool into the myocardium, lung, and
liver <5 min postinjection, after which a steady level of the tracer
was observed in blood, heart, and lung tissues as liver levels
decreased markedly over time (Figure 2). Importantly, the time-
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accumulate in cardiac tissue within minutes after injection.
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selective ligand ICI 89,406 were developed and evaluated as
potential cardiac imaging tracers. An extensive structureꢀactivity
study identified a series of fluorine-substituted β1-selective
ligands, with potent β1-AR affinity and β1/β2 selectivity. In vivo
evaluation of [18F]5ꢀ7 in SD rats demonstrated uptake of the
radiotracers in heart (0.48ꢀ0.62% ID/g), lung (0.63ꢀ0.97% ID/g),
and liver (1.03ꢀ1.14% ID/g) tissue; results were confirmed
through μPET imaging study.
Despite clear visualization of the myocardium, the consider-
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specific binding, which may limit overall application of current
imaging data and general utility of existing pharmacophore
design. Future studies will attempt to reconcile these issues of
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’ ASSOCIATED CONTENT
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S
Supporting Information. Full experimental procedures
b
and characterization data for all new compounds described in this
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LETTER
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