Complexes with oxocores

These are the most prevalent type of complex among potential radiopharma-ceuticals using rhenium, and these invariably involve Re(V). The ReO3+ core

dominates and many examples of both square pyramidal and octahedral geometries have been characterized, by including X-ray crystallography. The ReOj core can be stabilized by amine or tertiary phosphine co-ligands but has been less explored in a radiopharmaceutical context.

MAG3 type ligands

Mercaptoacetyltriglycine, MAG3, has been used extensively for the generation of 99mTc radiopharmaceuticals and selectivity is generated by bioconjugation to an appropriate bioactive molecule. The synthetic strategy generally adopted is summarized in Figure 24.2, which shows labelling via pre-conjugate formation. The rhenium is present as a mono-oxo species in the +V oxidation state with N3S coordination providing the characteristic square planar geometry. The X-ray crystal structure of the simple ReOMAG3 complex has been reported.8

Studies of both the pre- and post-conjugation labelling of peptides such as the RC-160 somastatin analogue with 188Re suggest that the pre-conjugation approach is preferable due to interaction with an S—S bond in the post-conjugation technique.9 Biodistribution studies in mice showed high tumour uptake comparable with values obtained for the direct labelling of RC-160.10

O

form activated ester form activated ester

O
Figure 24.3

An analogous approach has been used for the 188Re labelling of monoclonal antibodies using MAG3.11 Comparative studies of the radiolabelling of MORFs (synthetic oligomeric DNA analogues) with 90Y-DOTA (DOTA = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) and 188Re-MAG3 conjugates showed some disadvantages for both radionuclides. Self-radiolysis of the 90Y species led to loss of the radionuclide and the rhenium species underwent slow decomposition to perrhenate, but both were nevertheless essentially intact after 48 h.12

A modification of the MAG3-protein labelling procedure has been reported in which the cysteinyl group is replaced by a thiosemicarbazone, as shown in Figure 24.3. The tethering group was prepared by reaction of thiosemicarba-zide with glyoxylic acid and was subsequently linked to a bispecific antibody (bsMAB) via peptides which bind specifically to one arm of the antibody.13 The structure of the rhenium species formed on reaction with 188Re-perrhenate was not established, but work with rhenium thiosemicarbazone complexes suggests it may be a Re(V) mono-oxo species.14 Studies of biodistribution of the bsMAB-188Re conjugate in mice showed promising tumour to blood, kidney and liver ratios, suggesting good potential for the radioimmunotherapy of colorectal cancer.13

Aminethiolate complexes

The coordination chemistry of rhenium with N2S2 ligands has been well explored and the known types are summarized in Figure 24.4. The aminethio-late type have neutral charge whereas the charge on the amide thiolate complexes is dependent on the reaction conditions used, the monoanionic complex being obtained at higher values of pH. Despite the extensive chemistry known with non-radioactive rhenium, and in marked contrast to technetium, there appear to have been few recent examples of the use of amine or amide thiolate rhenium oxo-complexes for bioconjugate coupling to BAMs. An indirect approach is illustrated by the use of lipidol, which is an iodinated esterified lipid from poppy seed oil, that has been used a contrast agent for the detection of liver cancer. The synthesis of N2S2 amine thiolate rhenium complexes with long chain substituents (Figure 24.5a) confers solubility in lipidol which acts as

"SH

HS"

Ri Ri w

R1 = R2 = H, Me, R2 = H, COOH R3 = H, Me, R4 = H, Me, PhCH2

Figure 24.4

Figure 24.5

the delivery agent for the radiopharmaceutical. The biodistribution of such solutions was investigated in mice and high initial uptake in liver cancer was observed, but this was followed by washout and accumulation in the lung, but it was concluded that this approach was still of potential value for the treatment of liver cancer.15

The 'three plus one' and 'three plus two' approaches

This mixed ligand approach to targeting rhenium radioisotopes is exemplified by the complex shown in Figure 24.5b, prepared by reaction of an Re(V) precursor such as [ReO(gluconate)2]~ simultaneously with the tridentate ligand and the thiol RSH. Attachment of an appropriate functional group to the thiol R group then permits the introduction of the specific biological targeting group. This tactic has been studied extensively with conjugation to BAMs such as tropane derivatives for targeting dopamine transporter sites in the brain.16 The disadvantage in terms of clinical applications is that the monodentate thiolate ligand is prone to exchange with other thiols in biological media such as glutathione.

Dioxo complexes

A reproducible protocol for the synthesis of 186Re- or 188Re-labelled polyamine complexes of the type [ReO2N4]+ has been developed. Although acceptable yields were obtained for linear polyamines in water, the macrocyclic cyclam required the use of a two-phase water-dichloromethane solvent system with intermediate generation of [ReOCl3(PPh3)2]. Yields of 64% and radiochemical purity (RCP) of 96% were obtained with the macrocyclic cylam after chromatography. The complexes were shown to have high stability in serum.17

The dioxo core has also been used with P2S2 ligands (Figure 24.6) to produce bioconjugates with BAMs such as bombesin analogues. Bombesin, a 14 amino acid peptide, and structurally modified analogues show an enhanced response in a variety of tumour tissues. The major thrust of this work has been with 99mTc, but studies with 188Re have also been reported.

The presence of the reducing phosphine groups facilitates the perrhenate reduction and the dioxo-complex can be generated in good yield. Protein conjugation was carried out after binding of the radionuclide and the conjugate was formed in high yields. Biodistribution studies in mice with the analogous 99mTc species showed significant pancreatic uptake, suggesting that the complexes were being effectively targeted to gastrin releasing peptides (GRP) receptors.18

Direct labelling

This method has been widely used for radiolabelling of monoclonal antibodies with 186Re or 188Re. The antibody is treated with a reagent such as mercap-toethanol to reduce disulphide groups to thiol and then reacted with perrhenate in the presence of stannous chloride. The precise identity of the rhenium species present is not known, but a Re(V) mono-oxo species is likely. The direct labelling of peptides requires the peptide to have an amino acid sequence suitable for binding to the metal. Sequences such as Cys-Gly-Cys and Lys-Gly-Cys are incorporated in the required peptide at a location unlikely to

peptide

OH HO OH OH

peptide

OH HO OH OH

Figure 24.7

impair receptor binding and form mono-oxo chelates analogous to the MAG3 species discussed above.19

Steroid modelling

An interesting alternative to conjugation of a steroid to a rhenium chelate has been proposed whereby the peripheral groups on a mixed ligand complex are selected so that the whole complex simulates the shape and receptor-binding groups of the steroid.4 This is illustrated in Figure 24.7.

The mixed ligand Re(V) oxo-complex is formed preferentially in good yield using a 1:1 mixture of the bidentate ligands in good yield and the complex shows some affinity for steroid-binding receptors. It remains to be seen if this strategy can be extended to the targeting of other types of receptor as the synthetic challenges are considerable.

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