Multiparametric Labeling Optimization and Synthesis of 68Ga-Labeled Compounds Applying a Continuous-Flow Microfluidic Methodology

Abstract

The synthesis and functional evaluation of a wide variety of radiolabeled chelator-biomolecule conjugates with high specific activity and radiochemical purity are crucial to development of personalized nuclear medicine. An excellent platform technology for achieving this objective involves use of generator-produced positron emission tomography (PET)-radionuclide 68 Ga. Currently, applied manual methodology for optimization and development for new labeling techniques offers only slow screening with relatively high precursor consumption. A capillary-based microfluidic synthesis module with online high-performance liquid chromatography (HPLC) was constructed for the optimization of reaction parameters of 68 Ga-PET tracers. This approach enables performance of 68 Ga-labeling reactions in 10 μL volumes, followed by sample analysis. The high-throughput capacity of the system allows very rapid optimization. The optimal pH and ligand concentration from the experiments were utilized directly to the production of 68 Ga-NODAGA-(RGD) 2 and 68 Ga-NOPO-RGD. Applying optimal parameters to production of these aforementioned radiopharmaceuticals allowed their synthesis with high radiochemical purity (over 95%) and with surprisingly negligible retention of residual activity in the system.

PIDAZTA: Structurally Constrained Chelators for the Efficient Formation of Stable Gallium‐68 Complexes at Physiological pH

“…Notably, elevated temperatures have an almost negligible influence and do not substantially improve the labeling yield at lower concentrations, particularly for L2 (Figure ). Such behavior might be considered counterintuitive because it is fundamentally different from that of many established 68 Ga III chelators, particularly those based on polyazacycloalkanes, which exhibit the corresponding pH optimum at values around 3–4 and show a strong influence of temperature on the required chelator concentration (as a general rule, an approximately 30‐times lower concentration is required to achieve the same radiolabeling yield at 95 °C as compared to 25 °C) . An explanation might be that formation of L1 / L2 complexes from Ga n (OH) 3n (the prevalent form of 68 Ga III at neutral pH) and the competing dehydration of this hydroxide, yielding nonreactive, insoluble [Ga(O)OH] n (“colloidal 68 Ga”), are apparently accelerated to a comparable extent upon heating (Scheme ; d k 1 /d T ≈d k 2 /d T ), essentially resulting in similar labeling yields over a wide range of temperatures.…”

Microfluidic Synthesis of Nanomaterials for Biomedical Applications

“…Single‐phase or two‐phase reactors based on flow‐speed control and interfacial interactions will all contribute to nanostructures and particle shapes. [6b] Of course, microfluidics is also well used for labeling or analysis of the particles during the synthesis process . An example of good structural control under mild conditions is porous crystalline materials.…”