Complexes with cores containing metalnitrogen multiple bonds

Nitrido-complexes

The first example of a rhenium complex of this core was reported in the 1960s when [ReNCl2(PPh3)2] was prepared from [ReOCl3(PPh3)2] and a hydrazine salt20 and it was subsequently also prepared using azide as the nitride source.21 However, it has only been comparatively recently that this chemistry has been extended to the radioactive isotopes using a procedure developed for techne-tium. Reaction of [188ReO4p with a dithiocarbazate [H2NN(Me)CSSMe] generated the Re(V)N2+ core which was then stabilized by the addition of a dithiocarbamate salt to give the Re(V) species [ReN(S2CNR2)2] (R = Me, Et) in 95% yield.22 The biodistribution of the radiolabelled analogue, as expected, paralleled closely that of the known 99mTc analogue.

A potentially interesting approach to the targeting of rhenium nitride complexes is via Mixed PXP (where X = N or S) tridentate ligands combined with a bidentate ligand bearing a potential conjugation site (Figure 24.8).23

This chemistry has been thoroughly established for cold rhenium and for the 99mTc analogues, but there are no reports as yet of work with 188Re or biological studies of the labelled rhenium derivatives.

Diazenide and isodiazene derivatives

The ability of rhenium to form strong metal-nitrogen multiple bonds allied with the oxidizing ability of the higher oxidation states permits the synthesis of a range of rhenium and technetium complexes containing diazenide (NNR) or isodiazene (NNR2) ligands. Typical examples of rhenium complexes are shown in Figure 24.9.24,25 These ligands are electronically flexible and can bind with linear or bent M—N—N systems depending on the requirements of the metal centre. The linear forms predominate for simple terminally bound ligands, and virtually all the radiopharmaceutically relevant complexes discussed exhibit this geometry.

The chemistry of the bis(diazenido) and bis(isodiazene) complexes is complicated by the presence of the two N—N ligands and a recent advance has seen the synthesis of the monodiazenide complexes [ReCl2(NNAr)(MeCN)(PPh3)2] directly from perrhenate, hydrazine and triphenylphosphine.26 As well as

Ph2P

Ph2P

Figure 24.8

Figure 24.8

PPh,

PPh3

PPh3

Figure 24.10

Figure 24.10

providing a derivatisable core, an ester group in the 4-position of the aryl group of the diazenide ligand provides a potential conjugation site.26 The chloride and phosphine ligands can be substituted by a range of polydentate ligands,27 but this chemistry has yet to be extended to using rhenium radioisotopes.

The coordination chemistry of pyridylhydrazines has been well developed with both technetium and rhenium and the use of carboxyl substituents to attach targeting groups has been widely exploited in the HYNIC system (HYNIC = N-oxysuccinimidylhydrazinonicotinamide). This involves conjugation via an amide linkage by reaction of the carboxyl group on the pyridyl ring with an amino group of a protein such as chemotactic peptide via an activated ester. This procedure has been widely used for the development of specific imaging agents with 99mTc, but addition of a further co-ligand is necessary. The exact molecular structure of the technetium complex is not certain, but is believed to involve diazenide- or isodiazene-type coordination of the C5H4NNN fragment.

Reaction of perrhenate with pyridylhydrazine dihydrochloride gives the complex shown in Figure 24.10 in good yield.28 One of the pyridylNN units is chelated and protonated at the nitrogen adjacent to the metal and the other is bound analogously to the phenyl derivatives discussed above. The chloride ligands can be displaced by N-, S-donor ligands, giving access to a range of diazenide/diazene complexes. Although extensive use has been made of the HYNIC strategy for 99mTc, there are as yet few examples of its extension to radioactive rhenium isotopes. A comparison of 186Re radiolabelling of a murine A7 antibody with a MAG3 derivative and HYNIC suggested that the HYNIC conjugate, although easier to prepare, was less stable.29 Also, an investigation of the Re-188-HYNIC labelling of octreotide reported that there were difficulties with the co-formation of insoluble ReO2.30

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