In addition to coordination complexes, there is a significant amount of interest in preparing sandwich complexes of the Tc(CO)^ core.68,69 CpTc(CO)3 (Cp = cyclopentadienide) is an attractive and highly sought-after synthon for developing Tc-tagged radiopharmaceuticals because of the complex's small size and stability. The synthesis of organometallic complexes of 99mTc is challenging in that they must be prepared in aqueous media (organometallic complexes are traditionally prepared under anhydrous reaction conditions) where the concentration of the metal is very low.70
Wenzel was the first to report a method for synthesizing CpTc(CO)3 at the tracer level from 99mTcO4.71 The reaction (Scheme 18.2) involved heating 99mTcO4 in the presence of ferrocene as the source of Cp and Mn(CO)5Br as the CO reservoir. Spradau and Katzenellenbogen reported an enhanced version of the Wenzel reaction in which Cr(CO)6 was used as the source of CO and CrCl3 added as a reducing agent.72 The latter reaction conditions have been used as a means of preparing a variety of different sandwich compounds including an organometallic derivative of Octreotide.73 One of the major limitations of these methods is that they require the use of organic solvents and harsh reaction conditions which precludes routine clinical use and direct labeling of certain classes of biomolecules including peptides.
Fe SnCl2, THF or MeOH, heat
One of the reasons for needing such complex synthetic protocols is that Cp does not react readily with metals in aqueous solution and its conjugate base tends to oligomerize in water particularly when heated. Alberto and co-workers developed an ingenious solution to the problem by derivatizing the Cp ring with an acyl group which increases the stability of Cp thus preventing unwanted side reactions. Reaction of acyl-Cp derivatives with the Tc(CO)^ core afforded good to excellent yields of RC(O)CpTc(CO)3 complexes at both the macroscopic and tracer levels (Scheme 18.3).74 This approach was recently used to prepare a halfsandwich complex of technetium linked to a serotonergic ligand.75
As an alternative to Cp-type ligands, our group developed a means of preparing half-sandwich compounds of Tc using nido-carborane ligands of the general type (R2C2B9H10)~.76 When deprotonated, these ligands are iso-lobal to cyclopentadienide and they form sandwich-type compounds in which the metal is bound to the open face of the cluster. Carboranes are attractive ligands for radiometal chemistry because, unlike traditional organometallic ligands, they are compatible with the aqueous reaction environment and the products are typically more stable than the corresponding Cp complexes. One additional advantage of carboranes over traditional ligands is that they can be readily functionalized with a wide range of different groups at one or more of the carbon and/or boron vertices regioselectively. This affords a tremendous amount of flexibility when designing novel compounds.
Our original method for the synthesis of Tc-carborane complexes in water involved reacting [Tc(CO)3(OH2)3]+ with a nido-carborane in the presence of NaOH. The product [(^5-C2B9Hn)Tc(CO)3n, which can also be prepared having a linker arm for bioconjugation, was stable toward histidine and cysteine challenge experiments. The same reaction applied at the tracer level afforded only low yields of the 99mTc-carborane complexes. More recently, we discovered that fluoride can be used in place of hydroxide to promote the synthesis of Re/Tc-metallocarboranes at both the macroscopic and the tracer levels in water (Scheme 18.4).77 This is a significant discovery because it creates the opportunity to directly label carborane-biomolecule conjugates under mild reaction conditions. The 99mTc-labeled carboranes, like the 99Tc analogues, were produced in very high yields and they are stable to ligand challenge experiments.
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