Synthesis of the myoview ligand, (bisphosphinoethane-1,2- 14C)tetrofosmin

Article abstract of DOI:10.1002/jlcr.1199

The carbon-14 radiolabels in [bisphosphinoethane-1,2-¹⁴C] tetrofosmin ligand were readily introduced by reacting 1,2-dibromo[U- ¹⁴C]ethane with bis(2-ethoxyethyl)benzylphosphine (1). This was converted to the Myoview ligand in an ove

Full text of DOI:10.1002/jlcr.1199

Journal of Labelled Compounds and Radiopharmaceuticals
J Label Compd Radiopharm 2007; 50: 468–470.
Published online in Wiley InterScience
JLCR
(www.interscience.wiley.com). DOI: 10.1002/jlcr.1199
Short Research Article
Synthesis of the myoviewTM ligand, [bisphosphinoethane-
1,2-14C]tetrofosminy
GEOFFREY T. WOOLLEY*, SEAN L. KITSON and R. GORDON REID
GE Healthcare Limited, Amersham Place, Little Chalfont, Buckinghamshire HP7 9NA, UK
Received 22 August 2006; Revised 2 November 2006; Accepted 22 November 2006
Abstract: The carbon-14 radiolabels in [bisphosphinoethane-1,2-14C]tetrofosmin ligand were readily introduced by
reacting 1,2-dibromo[U-14C]ethane with bis(2-ethoxyethyl)benzylphosphine (1). This was converted to the
MyoviewTM ligand in an overall yield of 45%. This radiosynthesis was important in obtaining marketing approval
from the regulatory authorities and allowed MyoviewTM to become one of the main heart imaging agents of
today. Copyright # 2007 John Wiley & Sons, Ltd.
Keywords: MyoviewTM; tetrofosmin; gamma emitter; technetium-99m
Introduction
presence or absence of infarction under exercise and
rest conditions (Figure 1).1 This achievement was
recognized by winning the 1998 prestigious Queens
Award for Technical Achievement.2 One reason for the
success of MyoviewTM is that it uses the gamma emitter
technetium-99m rather than thallium-201.3,4
MyoviewTM is used in cardiology as an imaging agent to
study the heart in microscopic detail. The cardiac
imaging agent is labelled with technetium-99m com-
plexed to a biphosphine ligand tetrofosmin or P-53.
MyoviewTM is useful in the diagnosis and localization of
regions of reversible myocardial ischaemia in the
Many different phosphine ligands were prepared and
tested during the development of MyoviewTM and
tetrofosmin was found to be the most superior ligand
(Personal communication, P. G. Edwards, Department
of Chemistry, Cardiff University, UK).5
EtO
OEt
MyoviewTM highlights
P
P
P
EtO
OEt
*
Technetium-99m-labelled drug for myocardial per-
+
99mTc O2
fusion imaging for detection of Coronary Artery
Disease (CAD).6
*
Indicated for use with approved pharmacologic
stress agents for known or suspected CAD.6
EtO
P
OEt
OEt
*
High target-to-background ratio provides clear
images.4,6,7
Improved image clarity provides confident diagnosis.4,8
EtO
*
MyoviewTM
*
Demonstrates good sensitivity, specificity, and diag-
nostic accuracy.8
*
Imaging can begin as soon as 15 minutes or up to
4 hours after administration of MyoviewTM, enhancing
patient management and department flexibility. The
product was approved by the FDA in February 1996.
*Correspondence to: Geoffrey T. Woolley, GE Healthcare Limited, The
Maynard Centre, Forest Farm, Whitchurch, Cardiff CF14 7 YT, UK.
E-mail: geoff.woolley@ge.com
yProceedings of the Ninth International Symposium on the Synthesis
and Applications of Isotopically Labelled Compounds, Edinburgh,
16–20 July 2006.
The MyoviewTM is supplied as a kit containing
*
tetrofosmin, tin chloride and sodium hydrogen
Copyright # 2007 John Wiley & Sons, Ltd.

SYNTHESIS OF MYOVIEWTM LIGAND 469
carbonate. This lyophilized powder is sealed under
nitrogen and when sterile, pyrogen free sodium
pertechnetate Tc-99m in saline is added to the vial,
a Tc-99m complex of tetrofosmin is formed.1
sphine (1) (Scheme 1). This was readily prepared
from diethyl benzylphosphonate [PhCH2P(O)(OEt)2] by
reduction with lithium aluminium hydride to give
the intermediate benzylphosphine [PhCH2PH2] in 80%
yield. Then on subsequent photolysis in the presence of
ethyl vinyl ether gave bis(2-ethoxyethyl) benzylpho-
sphine (1) in 80% yield.5 The substrate bis(2-ethox-
yethyl)benzylphosphine (1) was heated at reflux in
acetonitrile with 1,2-dibromo[U-14C]ethane (100 mCi,
20m Ci/mmol) to afford [14C]compound(2) (97 mCi).
This salt was taken up in ethanol and treated with 30%
aqueous sodium hydroxide. After stirring at ambient
temperature and the removal of solvent the resulting
residue was treated with excess concentrated hydrochloric
acid. Aqueous work up gave [14C]compound (3) (80mCi).
14C-ligand Radiosynthesis
The starting material for [bisphosphinoethane-1,2-14C]
tetrofosmin (4) ligand was bis(2-ethoxyethyl)benzylpho-
[
14C]Compound (3) (44 mCi) in dry benzene was treated
with hexachlorodisilane and the resultant mixture was
heated at reflux for 30 minutes then cooled. The mixture
was hydrolysed with excess 30% aqueous sodium hydro-
xide and on aqueous work up followed by silica flash
column chromatography gave the ligand [bisphosphi-
noethane-1,2-14C]tetrofosmin (4) (25mCi) which was
radiochemically pure and satisfied our quality control
requirements.
Conclusion
Figure
1
Tomography image of a normal heart using
MyoviewTM. The agent localizes in myocardial muscle, and
areas of impaired activity appear as gaps in the horseshoe
shape. Figure available in colour online at www.interscience.
wiley.com
[bisphosphinoethane-1,2-14C]Tetrofosmin (4) was suc-
cessfully prepared in 45% overall yield from 1,2-dibromo
[U-14C]ethane. This material was used to demonstrate
OEt
OEt
OEt
14C
Br
+
Br
14C
14
+
P
Ph
C
Ph
P
14C
Ph
P
OEt
OEt
-
OEt
2Br
(1)
(2)
OEt
OEt
O
P
EtO
EtO
14
14
C
EtO
C
14
P
14
C
C
OEt
P
P
O
OEt
OEt
(4)
(3)
Scheme 1 Radiosynthesis of [bisphosphinoethane-1,2-14C]tetrofosmin (4).
Copyright # 2007 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2007; 50: 468–470
DOI: 10.1002.jlcr

470 G. T. WOOLLEY ET AL.
the safety profile of tetrofosmin. This radiosynthesis
helped MyoviewTM obtain marketing approval from
the regulatory authorities and subsequently became
one of the main heart imaging agents used today.
4. Higley B, Smith FW, Smith T, Gemmell HG,
Gupta PD, Gvozdanovic DV, Graham D, Hinge D,
Davidson J, Lahiri A. J Nucl Med 1993; 34: 30–38.
5. Chadwell SJ, Coles SJ, Edwards PG, Hursthouse MB,
Imran A. Polyhedron 1995; 14: 1057–1065.
6. MyoviewTM kit for the preparation of Technetium
Tc-99m Tetrofosmin for injection. http://www.
amershamhealthus.com/shared/pdfs/pi/Myoview.
pdf [20 August 2006].
REFERENCES
1. Ge Healthcare Bio-sciences. http://www.myoview.
com print [20 August 2006].
¨
¨
2. The neighbourhood newsletter from GE Healthcare,
April 2000.
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Schwaiger M. J Nucl Med 1997; 38: 428–432.
8. Jain D. Semin Nucl Med 1999; 29: 221–236.
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Copyright # 2007 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2007; 50: 468–470
DOI: 10.1002.jlcr