Organometallic approaches

Another approach which utilizes rhenium in a low oxidation state and mainstream organometallic chemistry is the use of the [CpRe(CO)3] core (Cp = cyclopentadienyl). In this system the ^-accepting properties of the cyclopentadienyl and carbonyl ligands are well suited to stabilizing the electron-rich Re(I) centre. Cyclopentadiene can be readily functionalized with various biologically active vectors which can then be used to make rhenium tricarbonyl cyclopentadienyl conjugates, and the small size and low molecular weight of the cyclopentadienyl ligand minimizes any potential steric interactions with the receptor-binding part of the biomolecule. A [CpRe(CO)3] derivative of Tamoxifen®, a drug widely used in the treatment of breast cancer, retains considerable binding affinity to the oestrogen receptor and an anti-proliferative activity in MCF-7-type cell lines comparable to Tamoxifen® (Figure 24.18).42

These compounds show some promise as non-radioactive anti-cancer agents but combining this activity with ^-emitting 188Re represents a considerable challenge. Cyclopentadienyl derivatives are often insoluble and unstable in water, which can prohibit the synthesis of these types of compounds in a radiopharma-ceutical context. An elegant approach to circumvent these problems involves using a cyclopentadienyl derivative that is deprotonated to a reasonable extent at physiological pH. This can be achieved by introducing electron-withdrawing substituents such as an a-carbonyl group. The 1-(2-methoxy-phenyl)piperazine

Figure 24.18

Figure 24.19

Figure 24.19

cyclopentadienyl derivative (Figure 24.19) reacts with [Re(CO)3(H2O)3]+ in a phosphate buffer (pH 7.4) and heating at 85 °C. The interest in aryl piperazines is due to their being receptor molecules for the 5-HT1A subclass of serotonergic

The synthesis of cyclopentadienyltricarbonylrhenium derivatives has recently been reported with 188Re. A cyclopentadienylcarboxylic acid rhenium tricarbo-nyl and its glycine conjugate were synthesized by utilizing a double ligand transfer reaction. For example, 1,1'-bis(methoxycarbonyl)ferrocene, chromium hexacarbonyl and tin(II) chloride were added to [188ReO4]~ in methanol and then sealed in a pressure tube and heated at 180 °C for 45min. Purification by column chromatography followed by hydrolysis of the ester and further purification by SepPak cartridge and reverse phase HPLC gave the product. This procedure is not amenable to routine radiopharmaceutical synthesis but the compounds were shown to be stable in murine plasma and their in vivo metabolism was studied in mice.45

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