Chemistry Reference
In-Depth Information
N
N
Cl
Cl
N
N
O
O
N
M
Tc
N
N
HO
2
C
N
N
PAr
3
N
Cl
NH
2
HO
O
N
NH
OH
Ar =C
6
H
4
SO
3
-4
45
46
47
fIgure 6.15
The HynIC ligand and 2-pyridylhydrazine derived complexes.
+
N
N
CO
2
Me
N
O
N
N
O
N
N
Re
Tc
O
S
S
PR
2
N
N
N
HO
O
S
O
S
S
H
S
OH
N
48
49
fIgure 6.16
A complex of a tethered HynIC type ligand and a cationic seven-coordinate Re complex.
The initial impetus for studying the Re chemistry of these ligand systems came from their involvement as intermediates
in the protonation of coordinated nitrogen (i.e., R = H). The first Re diazenide complexes [ReCl
2
(nnR)(Pme
2
Ph)
3
] (R = PhCo
[143], Ph [144]), prepared from the appropriate hydrazine, appeared in the early 1970s, and further papers describing mono
and bis(diazenide) Re complexes with a range of co-ligands followed [145-153]. Analogues of some of these complexes
with
99
Tc such as [TcCl(nnPh)(Ph
2
PCH
2
CH
2
PPh
2
)
2
]
+
and [TcCl(nnPh)
2
(PPh
3
)
2
] were also described and the possibility of
using the diazenide R group to attach biomolecules was discussed [154]. However, the major breakthrough in terms of radio-
pharmaceutical applications came with the introduction in the early 1990s of carboxylate-substituted hydrazinopyridines by
Zubieta, Babich, et al. - the so-called HynIC system (
45)
[155, 156]. The pyridylhydrazine is conjugated to the biological
targeting molecule via the carboxylate and reacted with
99m
Tco
4
−
, resulting in a stable metal nitrogen multiple bond. The
simplicity of this process has attracted extensive use
in vivo
(over 600 references to HynIC since 1990 in SciFinder). Some
representative targeting molecules and targets are RGD peptides for tumour imaging [138, 157, 158], gastrin peptides for
tumour imaging [159, 160], octreotide for somastatin receptors [161], annexin-V for apoptosis imaging [162, 163], EGF
protein for tumour imaging [164], and antimicrobial peptide UBI 29-41 for infection imaging [165]. There has also been a
useful recent review on the applications of HynIC [166].
Despite its widespread use, there some issues with HynIC that still have not been totally resolved. The number of
HynIC residues attached to the metal, their bonding mode, and state of protonation are difficult to define. Reaction of
[mo
4
]
−
with pyridylhydrazine hydrochloride gives the complexes [mCl
3
(nHnC
5
H
3
n)(nnC
5
H
3
nH)] (m = Tc, Re) (
46
),
which were fully structurally characterised [159, 167]. Detailed mass spectroscopic studies [168, 169] of the
99m
Tc complexes
with HynIC and a co-ligand have confirmed that oxo and chloride ligands are absent, but there is still ambiguity as to the
location of protons (Figure 6.16). An additional polydentate co-ligand such as tricine
47
or ethylenediamminediacetic acid
(EDDA) is required and a range has been studied [17], but many do not confer high stability and partial replacement by
donors within a conjugated peptide is possible. Also for asymmetric ligands there is the potential complication of the
presence of isomers. The tethering of an additional donor group to the HynIC molecule as in
48
has been examined, but this
does not remove the need for a further co-ligand. It would be desirable to have a coordinatively saturated complex to force
monodentate coordination with robust co-ligands and a positive overall charge to minimise protic equilibria. The
tris(dithiocarbamate) Re complex
49
, readily prepared from
44
with excess dithiocarbamate [170], is very stable in solution
and inert to protonation, and the Tc analogues might provide an alternative to the systems investigated hitherto. Although the
cold precursors, such as
46
(m = Re), have been studied, there have been very few studies of the extension of the HynIC
approach to Re, probably reflecting the stability and full characterisation problems discussed above.
The discussion of the chemistry of the HynIC system showed that it can involve both diazenide and isodiazene species
in protic equilibria. The use of 1,1-disubstitued hydrazines R
2
nnH
2
represents a direct route to isodiazene complexes that
