A mono-diazenide complex from perrhenate: Toward a new core for rhenium radiopharmaceuticals

Article abstract of DOI:10.1021/ic025995w

A new method for the synthesis of low to intermediate oxidation state rhenium complexes containing a bifunctional ligand has been developed. Reaction of [ReO₄]^- with substituted phenylhydrazines and triphenylphosphine in acetonitrile in the presence of HCl allows the isolation of [ReCl₂(NNC₆H₄-4-R) (NCCH₃)(PPh₃)₂] (where R = OCH₃, Cl, or CO₂CH₃). The substituted hydrazine acts as both a reductant and source of a monodentate diazenide ligand. The compounds have all been characterized in the solid state by X-ray crystallography and in the solution state by NMR, electrospray mass spectrometry, and HPLC. Cyclic voltammetry measurements show that the mono-diazenide complexes undergo a reversible oxidation.

Full text of DOI:10.1021/ic025995w

Inorg. Chem. 2003, 42, 929−931
A Mono-Diazenide Complex from Perrhenate: Toward a New Core for
Rhenium Radiopharmaceuticals
,‡
Andrew R. Cowley,† Jonathan R. Dilworth,* and Paul S. Donnelly‡
Inorganic Chemistry Laboratory, UniVersity of Oxford, South Parks Road, Oxford, U.K. OX1 3QR,
and Chemical Crystallography Laboratory, UniVersity of Oxford, U.K.
Received September 3, 2002
A new method for the synthesis of low to intermediate oxidation
state rhenium complexes containing a bifunctional ligand has been
This methodology has been used successfully in the
development of 99mTc imaging agents which use N-oxysuc-
cinimidylhydrazinonicotinamide (HYNIC) as the bifunctional
ligand.9,10 Similar systems have been investigated with
rhenium, whose coordination chemistry is superficially
similar to technetium, although rhenium is more kinetically
inert than technetium and significantly it is much harder to
reduce [ReO4]- than it is [TcO4]-.1 The coordination
chemistry of the HYNIC system is shown by the reaction of
[ReO4]- with 2-hydrazinopyridine which gives systems in
which two pyridylhydrazine derived units are coordinated
to the rhenium.11-13 X-ray structural characterization of the
compounds formed revealed a complex coordination chem-
istry due to the ability of the pyridylhydrazine derived ligands
to coordinate as either monodentate or bidentate ligands and
the existence of protic equilibria.14 This results in radiolabeled
protein conjugates made using this system consisting of
mixtures of complexes which have proved difficult to
characterize fully.
developed. Reaction of [ReO ]- with substituted phenylhydrazines
4
and triphenylphosphine in acetonitrile in the presence of HCl allows
the isolation of [ReCl2(NNC H -4-R)(NCCH )(PPh3)2] (where R )
6
4
3
OCH , Cl, or CO CH ). The substituted hydrazine acts as both a
3
2
3
reductant and source of a monodentate diazenide ligand. The
compounds have all been characterized in the solid state by X-ray
crystallography and in the solution state by NMR, electrospray
mass spectrometry, and HPLC. Cyclic voltammetry measurements
show that the mono-diazenide complexes undergo a reversible
oxidation.
There is much interest in the development of new
radiotherapeutic cancer agents based on rhenium. There are
two â-emitting isotopes of Re, 186Re and 188Re, which have
suitable nuclear properties for therapeutic applications. 188Re
is readily available from a generator by decay of 188W and
is obtained as a very dilute solution of [ReO4]-.1,2 This can
provide a useful source of sterilizing â radiation if it can be
targeted in vivo.3 Such targeting can be achieved by the
incorporation of the metal atom in a coordination complex
using a bifunctional ligand. Ideally the ligand must form a
highly stable complex and possess a point of further
functionalization that can allow the attachment of biologically
active molecules4 to provide specificity and selectivity in
vivo.1,5-8
We have previously reported the reaction of [ReOCl3-
(PPh3)2] with arylhydrazines (ArNHNH2) in methanol to give
the bis(diazenido) complexes [ReCl(N2Ar)2(PPh3)2].15 How-
ever, the substitution chemistry of these, like the pyridyl-
hydrazine derivatives, is complicated by protic equilibria and
somewhat unpredictable loss of diazenide with some ligand
systems. We here report the reaction of arylhydrazines
directly with perrhenate in acetonitrile to give a high yield
of a mono aryl diazenide complex. This undergoes extensive
high-yield substitution reactions16 and has the potential to
* Author to whom correspondence should be addressed. E-mail:
jon.dilworth@chem.ox.ac.uk.
(9) Liu, S.; Edwards, D. S.; Barrett, J. A. Bioconjugate Chem. 1997, 8,
621.
(10) Babich, J. W.; Coco, W. G.; Barrow, S.; Fischman, A. J.; Femia, F.
L.; Zubieta, J. Inorg. Chim. Acta 2000, 309, 123.
† Chemical Crystallography Laboratory.
‡ Inorganic Chemistry Laboratory.
(1) Dilworth, J. R.; Parrott, S. J. Chem. Soc. ReV. 1998, 27, 43.
(2) Blower, P. J.; Dilworth, J. R.; Maurer, R. I.; Mullen, G. D.; Reynolds,
C. A.; Zheng, Y. J. Inorg. Biochem. 2001, 85, 15.
(3) Volkert, W. A.; Hoffman, T. J. Chem. ReV. 1999, 99, 2269.
(4) Rader, C.; List, B. Chem. Eur. J. 2000, 6, 2091.
(5) Parker, D. In ComprehensiVe Supramolecular Chemistry; Reinhoudt,
D. N., Ed.; Pergamon Press: Cambridge, 1996; Vol. 10.
(6) Reichert, D. E.; Lewis, J. S.; Anderson, C. J. Coordin. Chem. ReV.
1999, 184, 3.
(11) Nicholson, T.; Cook, J.; Davison, A.; Rose, D. J.; Maresca, K. P.;
Zubieta, J.; Jones, A. G. Inorg. Chim. Acta 1996, 252, 421.
(12) Nicholson, T.; Cook, J. D.; Davison, A.; Rose, D. J.; Maresca, K. P.;
Zubieta, J.; Jones, A. G. Inorg. Chim. Acta 1996, 252, 427.
(13) Hirsch-Kuchma, M.; Nicholson, T.; Davison, A.; Davis, W. M.; Jones,
A. G. Inorg. Chem. 1997, 36, 3237.
(14) Rose, D. J.; Maresca, K. P.; Nicholson, T.; Davison, A.; Jones, A.
G.; Babich, J. W.; Fischman, A. J.; Graham, W.; DeBord, J. R. D.;
Zubieta, J. Inorg. Chem. 1998, 37, 2701.
(7) Jurisson, S.; Berning, D.; Jia, W.; Ma, D. Chem. ReV. 1993, 93, 1137.
(8) Anderson, C. J.; Welch, M. J. Chem. ReV. 1999, 99, 2219.
(15) Dilworth, J. R.; Harrison, S. A.; Walton, D. R. M.; Schweda, E. Inorg.
Chem. 1985, 24, 2594.
10.1021/ic025995w CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/29/2003
Inorganic Chemistry, Vol. 42, No. 4, 2003 929

COMMUNICATION
Scheme 1. The Synthesis of 1-3
provide access to a new core for the development of radio-
therapeutic agents based on rhenium.
When [NH4][ReO4] or [nBu4N][ReO4] is reacted with
substituted phenylhydrazines (NH2NHC6H4-4-R, where R )
OCH3, Cl, or CO2CH3) in acetonitrile in the presence of
aqueous acid, a red color rapidly develops. The electrospray
mass spectra of the reaction mixture when R ) OCH3 show
that several different rhenium diazenide species are present,
but by far the biggest peak (in negative ion mode, with
appropriate isotope distribution) corresponds to the mono-
diazenide species [Re(NNC6H4-4-OCH3)Cl4]- at m/z ) 462.
Other less intense peaks in positive ion mode are assignable
to [Re(NNC6H4-4-OCH3)2(NCCH3)2]+ and [Re(NNC6H4-4-
OCH3)(NCCH3)2 + Na+]+. HPLC measurements of the
reaction mixture at this stage show a peak due to perrhenate
(0.73 min, 90:10 CH3CN/H2O) and four other species with
retention times (in the case of R ) OCH3) of 1.50, 1.67,
1.87, and 2.33 min in an isocratic eluent mixture of 90:10
CH3CN/H2O. The presence of perrhenate may indicate that
the reaction does not go to completion or, more likely, that
some dissociation of the intermediates occurs under the
aerobic aqueous HPLC conditions. Addition of triphenylphos-
phine results in the formation of a single species by HPLC
and red air-stable solids in isolated yields of about 70%
(Scheme 1). It appears that the triphenylphosphine may
stabilize the diazenide core and drive the reaction in Scheme
1 to completion. Similar observations have been made from
other species with metal-nitrogen multiple bonds.17 Interest-
ingly, these compounds are not accessible from the reaction
of the well-known rhenium precursor, [ReOCl3(PPh3)2], with
arylhydrazines in acetonitrile.
In this system the arylhydrazine acts both as a reductant,
reducing the Re(VII) of the [ReO4]- starting material,
meaning that no external reducing agents are required, and
as a precursor to the diazenide ligand. The complexes are
diamagnetic, and 1H NMR spectra in CDCl3 are well-
resolved, showing signals for the AA′BB′ system of the
4-substituted phenyl ring at about δ 6.4 ppm. The signals
due to the trans triphenylphosphine ligands come within the
expected range, and in the case of compounds 1 and 3 a
singlet is observed for the OCH3 group and the CO2CH3
group. The major peak in the electrospray mass spectra
(positive ion mode) of the red solids in each case corresponds
to [ReCl2(NNC6H4-4-R)(PPh3)2 + H+].
Figure 1. An ORTEP-3 representation of 1. Hydrogen atoms and solvent
molecules have been omitted for clarity.
Figure 2. An ORTEP-3 representation of 3. Hydrogen atoms and solvent
molecules have been omitted for clarity.
Table 1. Summary of the Bond Distances for the Re-N-N Fragment
compound
Re1-N1 (Å)
N1-N2 (Å)
1
2
3
1.789(2)
1.775(3)
1.786(7)
1.225(3)
1.240(4)
1.22(1)
Each of the compounds has been structurally characterized
by X-ray crystallography, and all have similar structures.
ORTEP-3 representations of the X-ray crystal structures of
1 and 3 are shown in Figures 1 and 2.
In all cases the rhenium is in a distorted octahedral
environment with the two triphenylphosphine ligands trans
to each other, a coordinated chloride trans to the diazenide
ligand, another chloride, and a coordinated acetonitrile
molecule. In all three compounds the Re-N-N system is
essentially linear (Re1-N1-N2 ) 167.8(2)° in 1, 168.5(2)°
in 2, and 168.8(6)° in 3) and the Re-N and N1-N2 bond
distances are characteristically short (see Table 1), consistent
with the monodentate diazenide ligand acting as a monoan-
ionic 3 electron donor. The fact that the complexes are
isolated in the presence of excess hydrochloric acid suggests
that no facile protonation of the diazenide occurs.
(16) Cowley, A. R.; Dilworth, J. R.; Donnelly, P. S.; Ross, S. J.; Tisato,
F.; Ward, C. V. Manuscript in preparation.
(17) Boschi, A.; Bolzati, C.; Benini, E.; Malago, E.; Uccelli, L.; Duatti,
A.; Piffanelli, A.; Refosco, F.; Tisato, F. Bioconjugate Chem. 2001,
12, 1035.
930 Inorganic Chemistry, Vol. 42, No. 4, 2003

COMMUNICATION
The X-ray crystal structure of 3 shows that the pendant
ester substituent lies in an extended position, pointing away
from the rest of the complex. This means that it should
provide a readily accessible site for further functionalization
with a biologically active molecule such as a monoclonal
antibody or protein that could provide specificity in vivo.
The stability of rhenium diazenide complexes means that
any biologically active molecules tethered to the rhenium in
this fashion should remain bound in vivo.
These new compounds provide a new “rhenium core”
which can be readily substituted with a variety of ligands to
form kinetically inert species and to control several important
factors such as complex stability, hydrophilicity, charge, and
ultimately biodistribution. Importantly, with respect to the
potential use of these systems as new radiotherapeutic agents,
the synthesis can be readily achieved from [ReO4]- in high
yields. The fact that this method produces a monodentate
mono-diazenido species means that these systems may well
provide better defined species than the well-studied Re-
HYNIC systems.14,18
Figure 3. Cyclic voltammograms of 1 (dashed line) and 2 (solid line).
Potentials are quoted versus an internal ferrocene reference.
Cyclic voltammetry measurements of 1 and 2 (Figure 3)
show that the mono-diazenide species undergo a fully
reversible oxidation which is tentatively assigned to a Re(III)/
Re(IV) processs.
The 4-chloro-substituted complex (2) undergoes a revers-
ible oxidation at +0.18 V versus an internal ferrocene
reference (0.60 V versus SCE) while the electronic effects
of the methoxy group of 1 are manifested in oxidation at a
slightly lower potential, +0.14 V versus an internal ferrocene
reference (0.56 V versus SCE). The fully reversible nature
of the oxidation process reflects the stability of the Re(IV)
cation.
Supporting Information Available: Crystallographic data
(PDF and CIF). This material is available free of charge via the
Internet at http://pubs.acs.org.
IC025995W
(18) Kovacs, M. S.; Hein, P.; Sattarzadeh, S.; Patrick, B. O.; Emge, T. J.;
Orvig, C. J. Chem. Soc., Dalton Trans. 2001, 3015.
Inorganic Chemistry, Vol. 42, No. 4, 2003 931