Fluorous-Phase Purification of ⁹⁹ᵐTc Radiopharmaceuticals

Abstract

<p>To produce Tc-based radiopharmaceuticals in high effective specific activity the excess precursor ligand must be removed. A new and convenient solid-phase ligand capture method of a resin-bound Cu chelate was recently developed to remove unlabeled ligand.[1] Herein, the impact ofsize on the purification was evaluated using three welldefined resin sizes and a model chelate system, where the average capture efficiency was 89.1 ± 3.3% and loss due to non-specific binding was 23.4 ± 1.6%.</p> <p>A complementary solution-phase strategy was developed employing fluorous chemistry to remove unlabeled chelate-derivatives with less loss of product. The novel fluorous analog to the solid-phase copper chelate was synthesized in three steps (70% overall yield). Using the same model Tc(I) chelate, >99% ofthe ligand was captured by the fluorous ligand capture (FLC) method and the extent of non-specific binding was 65% lower than the solid-phase equivalent. A peptide conjugate was then used to further test the general utility ofthe FLC method with comparable ligand removal (95.1 ±0.8%) and non-specific binding (12.1 ± 1.2%).</p> <p>Attempts were made to automate the FLC method using a microfluidic device with no detrimental effect to either the radiochemical yield (4.15 ± 1.0% non-specific binding) or the efficiency of ligand capture (99.74 ± 0.04%). A second strategy involved preloading the FLC agent onto fluorous silica and capturing the excess ligand (99.85 ± 0.02%) and peptide (95± 1%) as the radiolabeling mixture was washed over the cartridge with 2.25 ± 0.55% and 33.3 ± 3.2% product lost, respectively. This approach can now be incorporated into a new generation of instant kits or an integrated microfluidic preparation of molecular imaging probes in high effective specific activity.</p>