(568r) A Microreactor for the Synthesis of Radiometal-Based Nuclear Imaging Agents

Radiopharmaceuticals, used in nuclear medicine as imaging agents for Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT), consist of a disease- or tissue-specific targeting molecule, such as a peptide, antibody, or metabolite, that is labeled with a radioactive isotope. For labeling with radiometals, a bifunctional chelator that selectively binds the radiometal of interest is conjugated to the targeting biomolecule. In conventional, macro-scale radiolabeling methods, an excess of the biomolecule-bifunctional linking molecule (ligand) is typically used to achieve high radiolabeling yields. Consequently, in order to achieve maximal specific activity (minimal number of unlabeled molecules), extensive chromatographic purification of the product is often required to remove unlabeled ligand, resulting in longer synthesis times and the ensuing loss of radioactivity due to decay. We will present the development of a simple, semi-batch microreactor made from PDMS and glass that overcomes these issues through efficient mixing and heating of small, concentrated volumes of reagents. Using the radiolabeling of 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA) conjugated to the peptide cyclo(Arg-Gly-Asp-DPhe-Lys) (forming DOTA-cyclo(RGDfK)) with the radiometal Cu-64 as a test reaction, we will demonstrate that (1) the materials used to construct the microreactor are able to withstand up to 260 mCi of activity, over 720 hours; (2) while positively-charged Cu-64 ions bind electrostatically to the negatively-charged glass surface of the microreactor, once this surface is saturated, no further interaction between the microreactor and radiometal occurs, resulting in minimal retention of the radiometal (< 5 %); and (3) by using small volumes (~10 µL) of concentrated solutions (~50 µM), the microreactor obtains extents of reaction of over 90%, using a 1:1 stoichiometry, moderate temperatures (37 °C) and a residence time of 12 minutes. High yields at a 1:1 stoichiometry obviate the need for a chromatographic purification process to remove unlabeled ligand. We will also provide a direct comparison between the extent of reaction obtained using the microreactor and those obtained using conventional, macro-scale radiolabeling methods; from this comparison, we conclude that improved mixing and heat transfer in the microreactor lead to higher extents of reaction for identical radiolabeling conditions. We will also present the development of a microreactor for the click chemistry-based conjugation of biomolecules with bifunctional chelators. In total, these results demonstrate the strong potential of microfluidic systems to improve and automate the production of patient-tailored doses of radiometal-based radiopharmaceuticals in the clinic.