[¹⁸F]FLUDA - A novel radiotracer for PET imaging of the adenosine A₂A receptor (A₂AR)

Introduction: Selective A₂AR antagonists have emerged as potential therapeutics for multiple diseases. With regard to Parkinson’s disease, adjunctive treatment of A₂AR antagonists potentially reduces adverse effects of long-term L-DOPA treatment. Therefore, imaging of receptor availability during the A2AR-tailored therapy is of utmost importance. We recently developed [¹⁸F]FLUDA as an novel A₂AR-specific PET radiotracer [1].
Methods: [¹⁸F]FLUDA was synthesized by an automated procedure Biological evaluation was performed in healthy mice and piglets. In vitro autoradiography was performed with brain cryosections. In vivo metabolism was analysed by radio-HPLC of plasma and brain homogenate. Pharamcokinetics and biodistribution was assessed by dynamic PET imaging under control and blocking conditions (2.5 mg/kg tozadenant and/or 1.0 mg/kg istradefylline). SUV ratio (SUVr) of striatum-over-cerebellum was used as a metric for specific uptake. A single dose acute toxicity study was performed in Wistar rats according to the ICH guideline M3(R2). Radiation dosimetry was investigated in piglets.
Results: In vitro autoradiography revealed an A₂AR affinity (KD;) of 4.3 and 0.7 nM and an A₂AR density (Bmax) of 556 and 218 fmol/mg in the striatum of mice and piglets. No radiometabolites were detected in the mouse brain at 15 min p.i., whereas radiometabolites were found in piglet plasma but are assumed to not cross the blood-brain barrier. PET demonstrated high specific binding of [¹⁸F]FLUDA in both species (Fig.1). Toxicity studies revealed no adverse effects up to a dose of 30 µg/kg (~4000-fold of expected human dose). The ED to humans is 16.4 µSv/MBq, which is in the range of other ¹⁸F-labeled radiotracers [2].
Conclusion: We have demonstrated that [¹⁸F]FLUDA is suitable for determination of the A₂AR availability in the striatum. No safety concerns are expected upon administration of [¹⁸F]FLUDA according to toxicity and dosimetry data. These results encourage the clinical translation of [¹⁸F]FLUDA.
Acknowledgement: This work (Project No. 100226753) has been funded by the European Regional Development Fund (ERDF) and Sächsische Aufbaubank (SAB).
References: [1] Lai, T.H., Toussaint, M., Teodoro, R., Dukić-Stefanović, S., Gündel, D., Ludwig, F.-A., Wenzel, B., Schröder, S., Sattler, B., Moldovan, R.-P., Falkenburger, B.H., Sabri, O., Winnie Deuther-Conrad, W., Peter Brust, P. Improved in vivo PET imaging of the adenosine A₂A receptor in the brain using [¹⁸F]FLUDA, a deuterated radiotracer with high metabolic stability. Eur J Nucl Med Mol Imaging 2021, 48, 2727–2736. [2] Sattler, B., Kranz, M., Lai, T.H., Gündel, D., Toussaint, M., Schröder, S., Moldovan, R.-P., Winnie Deuther-Conrad, W., Teodoro, R., Sabri, O., Peter Brust, P. Preclincal incorporation dosimetry of [¹⁸F]FLUDA - a novel ¹⁸F-labeled tracer for PET imaging of the expression of the adenosine A₂A receptor (A₂AR). J Nucl Med 2020, 61:1014.