There has been a lot of interest engendered by the relatively recent development of methods that allow the synthesis of technetium or rhenium compounds of the type /ac-[M(CO)3(H2O)3]+ (where M = Tc(I) or Re(I)) under conditions amenable to the radiopharmaceutical applications. The use of what has become
oh2 Figure 24.11
known as the 'carbonyl core' approach exploits the stability of the metal tricarbonyl core whilst manipulating the relatively labile water ligands to attach pertinent biomolecules (Figure 24.11). A variety of mono-, bi- and tri-dentate ligands react with the tricarbonyl core, displacing the substitutionally labile aqua ligands. The small size of the core should allow tethering of radiometals to biomolecules without deleterious effects on their activity and specificity.
These organometallic derivatives provide a novel approach to the design of radiopharmaceuticals. One of the most significant features of the chemistry has been the development of methods that allow synthesis of the carbonyl compounds under relatively mild conditions from pertechnetate or perrhenate, which are the starting materials for radiopharmaceutical preparations.31
One synthetic procedure involves reacting a tetrahydrofuran (THF) solution of [NBu4][MO4] (M = Re(VII) or Tc(VII)) with a carbon dioxide purged solution of tetrabutylammonium chloride using borane in THF as the reducing agent. [NEt4]2[fac-MBr3(CO)3] can be isolated following acidification and addition of [NEt4]Cl. The synthesis of the rhenium compound requires longer reaction times (about 4 h) than does the synthesis of the technetium analogue (about 2h). In aqueous solutions this compound rapidly exchanges the halides for water ligands to give the useful precursor [fac-M(CO)3(OH2)3]+ (M = Re(I) or Tc(I)).32
Further modifications have been directed towards developing a procedure that eliminates the requirement to use gaseous carbon monoxide, which is unsuitable for use in commercial radiopharmaceutical 'kits'. The technetium carbonyl compound fac-[Tc(CO)3(OH2)3]+ can be prepared by using the innovative approach of using a boron-based carbonylating agent, boranocarbonate K2[H3BCO2], which acts as a source of carbon monoxide and as a reducing agent.33 This development has allowed the introduction of the 'Isolink kit®' for the synthesis of technetium carbonyl compounds. The kit is commercially available from Mallinckrodt Medical B.34 The same technology can be adapted to rhenium although this is not straightforward. Problems arise because perrhenate is harder to reduce than pertechnetate and any Re(III) or Re(V) complexes formed during the reductive carbonylation are unstable at basic pH. These problems can be circumvented by using aminoborane as the reducing agent and careful control of the pH (Figure 24.12).35
The /ac-[Re(CO)3(H2O)3]+ cation has been referred to as a 'semi aquo ion' with three tightly held CO ligands and three labile coordination sites. Carbonyl ligands are known to stabilize low oxidation states via backbonding mechanisms and the trans effect increases the lability of the trans ligands allowing them to be readily substituted. This allows the attachment of a wide variety of ligands to the carbonyl core. The Re(I) complexes have d6 low spin octahedral configurations, which are known to form stable complexes.
The ligand exchange reactions in these systems occur via a dissociative mechanism and for radiopharmaceutical applications, rapid exchange to form stable complexes is essential. It has been shown that aliphatic amines, carbox-ylates and other anions only coordinate weakly to the /ac-[Re(OH2)3(CO)3]+ core. In contrast, thioether ligands were found to coordinate very slowly but the resulting complexes exhibited high stability. It has been suggested that the best ligands for the/ac-[M(CO)3]+ core are aromatic amines as they exhibit fast complexation kinetics to form reasonably stable complexes and that any anchoring of biomolecules to the /ac-[Re(CO)3]+ core should be done via a unit that contains at least one aromatic amine. Furthermore, the combination of an aromatic amine with an aliphatic amine or carboxylate group gave complexes that formed quickly whilst having high stability in aqueous solutions.31
A particularly good ligand is histidine, which binds facially as a tridentate ligand. This offers the potential of anchoring biomolecules to the [Re(CO)3]+ core via a histidine residue (Figure 24.13).31
If the carboxyl group of histidine is used in the formation of an amide bond as part of a protein sequence then the histidine residue binds as a bidentate ligand. Radiolabelling studies have been carried out with an N-terminal His-peptide by incubating [Tc(CO)3(H2O)3]+ with His-Gly-Gly-Ala-Ala-Leu for 90min at 37 °C. This has been extended to the radiolabelling single-chain antibody fragments carrying a C-terminal His-tag. These conjugates displayed neither trans chelation nor loss of binding affinity.36 It is anticipated that this labelling technology could be readily extended to 186/188Re to provide radio-therapeutic analogues of the technetium imaging agents.
The [188Re(CO)3] core has been labelled by tridentate bifunctional ligands based on either bis(imidazol-2-yl)methylamine or iminodiacetic acid ligands with alkyl spacers of different lengths and a pendant primary amino or carb-oxylic acid functionality (Figure 24.14). The optimum radiolabelling conditions were shown to be incubating [188Re(CO)3(H2O)2] with the ligand in a phosphate buffer at 60 °C for 60min. Shorter incubation at higher temperatures (100 °C) or longer incubation at lower temperatures (37 °C) resulted in poor radiolabelling yields due to the oxidation of the rhenium carbonyl precursor to perrhenate. The bis(imidazol-2-yl)methylamine complexes are more stable than the iminodiacetic acid complexes, the former showing about 20% degradation in human serum over 24 h, the major decomposition product being perrhenate.35
A wide variety of other ligands that coordinate to the/ac-[Re(CO)3] core and have the potential to act as the basis of new radiopharmaceuticals have been reported. Some selected examples are discussed in the following paragraphs.
Tridentate ligands bearing two pyridyl groups derived from amino acids or amino acid analogues react with [Et4N]2[ReBr3(CO)3] cleanly and in high yield to give complexes of the type [Re(CO)3L]+. The [Re(CO)3L]+ complex with Fmoc-Lysine (Fmoc = 9-fluorenylmethoxycarbonyl)-derived ligand of this type (Figure 24.15) has been used to incorporate the rhenium carbonyl core into a short peptide sequence through automated solid phase methods. This flexible approach should allow the rhenium chelate to be incorporated at any position in a peptide sequence.37
Poly(mercaptoimidazolyl)borate ligands form complexes of the type [Re(L)(CO)3], where the ligands act as a facially coordinating tridentate via the two sulphur donor and an unusual agostic B—H ••• Re bond (Figure 24.16).38 These ligands have been further functionalized to include central nervous system receptor-avid molecules.39
[NEt4]2[Re(CO)3Br3] has been shown to react with 2-acetylpyridine phenyl-thiosemicarbazone to form air-stable, neutral Re(I) complexes of the composition [Re(CO)3(L)]. The thiosemicarbazone ligand deprotonates and binds to the metal in a facial manner as a tridentate N, N, S donor (Figure 24.17). To accommodate the facial coordination geometry the ligand considerably distorts from planarity, which is unusual for the extensively conjugated thiosemicarbazone ligand.40
The examples listed here clearly show that the 'tricarbonyl core approach' offers considerable potential in the development of rhenium radiopharmaceuticals but the commercial viability of the analogous approach to technetium imaging radiopharmaceuticals has been questioned. Problems in the commercial development of imaging agents based on the [Tc(CO)3]+ core include intellectual property issues and regulatory hurdles.34,41 The same issues may also hinder the development of rhenium tricarbonyl-based therapeutics and more work is required on a synthesis of [188Re(CO)3(H2O)2]+ that can be performed on a routine basis. However, this versatile technology could lead to clinically viable therapeutic agents which could be developed in concert with the analogous technetium-based imaging agents.
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