Taking Ga-68 labeling optimization to the fast line with a new microfluidic system

Objectives To accelerate the development of novel ⁶⁸Ga-radiopharmaceuticals, i.e. the optimization of labeling conditions and radiochemical yields by means of a time-efficient technique that offers high reproducibility, a microfluidic synthesis module with on-line HPLC was constructed and evaluated. Here we present the first results towards a simplified screening and production technique of ⁶⁸Ga-PET tracers.

Methods The fully automatic microfluidic system consists of an autosampler, HPLC injector valves, an air thermostat and a 15 x 0.15 m PEEK tube. The system works by co-injection of equivalent µL volumes of a HEPES-buffered chelator solution and a ⁶⁸Ge/⁶⁸Ga-generator eluate into a constant carrier flow (water at 0,033 mL/min for 5 min reaction time) and subsequent complexation in the reactor tube. The reaction mixtures are collected or automatically injected onto a Waters HPLC system, where separation of unbound ⁶⁸Ga and labeled tracers are performed on an Adsorbosphere XL SCX 5u 250x4,6 mm column with a gradient mixed from 0.2 M aq. tartaric acid, water and 5% aq. NaCl.

Results The comparison of manual and microfluidic labeling of NOTA and NOPO revealed improved reproducibility and allowed for fast optimization of reaction parameters when the self-made microfluidic system was employed. 3D graphs depicting detailed labeling yield plots for pH and [ligand] could be obtained via fully automated evaluation. Subsequently, optimum production parameters were transferred to the production of ⁶⁸Ga-NOPO-RGD and ⁶⁸NODAGA-RGD, resulting in >95% RCY and negligible activity retention in the µF-system.

Conclusions We successfully constructed, tested and evaluated an automated, capillary based production system for the evaluation and optimization of ⁶⁸Ga-complexation reactions. The presented method is a valuable tool for fast, efficient, cost-effective and reliable screening of labeling parameters employed during the development of novel ⁶⁸Ga-PET radiopharmaceuticals.