To expand the biomedical applications of pH responsive polymersomes a concept is presented for precisely adjusting the pH triggered transition of the membrane permeability.

Purpose: The adenosine A_2A receptor has emerged as a therapeutic target for multiple diseases, and thus the non-invasive imaging of the expression or occupancy of the A_2A receptor has potential to contribute to diagnosis and drug development. We aimed at the development of a metabolically stable A_2A receptor radiotracer and report herein the preclinical evaluation of [¹⁸F]FLUDA, a deuterated isotopologue of [¹⁸F]FESCH. Methods: [¹⁸F]FLUDA was synthesized by a two-step one-pot approach and evaluated in vitro by autoradiographic studies as well as in vivo by metabolism and dynamic PET/MRI studies in mice and piglets under baseline and blocking conditions. A single-dose toxicity study was performed in rats. Results: [¹⁸F]FLUDA was obtained with a radiochemical yield of 19% and molar activities of 72–180 GBq/μmol. Autoradiography proved A_2A receptor–specific accumulation of [¹⁸F]FLUDA in the striatum of a mouse and pig brain. In vivo evaluation in mice revealed improved stability of [¹⁸F]FLUDA compared to that of [¹⁸F]FESCH, resulting in the absence of brain-penetrant radiometabolites. Furthermore, the radiometabolites detected in piglets are expected to have a low tendency for brain penetration. PET/MRI studies confirmed high specific binding of [¹⁸F]FLUDA towards striatal A_2A receptor with a maximum specific-to-non-specific binding ratio in mice of 8.3. The toxicity study revealed no adverse effects of FLUDA up to 30 μg/kg, ~ 4000-fold the dose applied in human PET studies using [¹⁸F]FLUDA. Conclusions: The new radiotracer [¹⁸F]FLUDA is suitable to detect the availability of the A_2A receptor in the brain with high target specificity. It is regarded ready for human application.

Glioma are clinically challenging tumors due to their location and invasiveness nature, which often hinder complete surgical resection. The evaluation of the isocitrate dehydrogenase mutation status has become crucial for effective patient stratification. Through a transdisciplinary approach, we have developed an ¹⁸F-labeled ligand for non-invasive assessment of the IDH1R132H variant by using positron emission tomography (PET) imaging. In this study, we have successfully prepared diastereomerically pure [¹⁸F]AG-120 by copper-mediated radiofluorination of the stannyl precursor 6 on a TRACERlab FX2 N radiosynthesis module. In vitro internalization studies demonstrated significantly higher uptake of [¹⁸F]AG-120 in U251 human high-grade glioma cells with stable overexpression of mutant IDH1 (IDH1R132H) compared to their wild-type IDH1 counterpart (0.4 vs. 0.013% applied dose/µg protein at 120 min). In vivo studies conducted in mice, exhibited the excellent metabolic stability of [¹⁸F]AG-120, with parent fractions of 85% and 91% in plasma and brain at 30 min p.i., respectively. Dynamic PET studies with [¹⁸F]AG-120 in naïve mice and orthotopic glioma rat model reveal limited blood-brain barrier permeation along with a low uptake in the brain tumor. Interestingly, there was no significant difference in uptake between mutant IDH1R132H and wild-type IDH1 tumors (tumor-to-blood ratio_{[40−60 min]}: ~1.7 vs. ~1.3). In conclusion, our preclinical evaluation demonstrated a target-specific internalization of [¹⁸F]AG-120 in vitro, a high metabolic stability in vivo in mice, and a slightly higher accumulation of activity in IDH1R132H-glioma compared to IDH1-glioma. Overall, our findings contribute to advancing the field of molecular imaging and encourage the evaluation of [¹⁸F]AG-120 to improve diagnosis and management of glioma and other IDH1R132H-related tumors.

The adenosine A_2A receptor (A_2AR) is regarded as a particularly appropriate target for non-dopaminergic treatment of Parkinson’s disease (PD). An increased A_2AR availability has been found in the human striatum at early stages of PD and in patients with PD and dyskinesias. The aim of this small animal positron emission tomography/magnetic resonance (PET/MR) imaging study was to investigate whether rotenone-treated mice reflect the aspect of striatal A_2AR upregulation in PD. For that purpose, we selected the known A_2AR-specific radiotracer [¹⁸F]FESCH and developed a simplified two-step one-pot radiosynthesis. PET images showed a high uptake of [¹⁸F]FESCH in the mouse striatum. Concomitantly, metabolism studies with [¹⁸F]FESCH revealed the presence of a brain-penetrant radiometabolite. In rotenone-treated mice, a slightly higher striatal A_2AR binding of [¹⁸F]FESCH was found. Nonetheless, the correlation between the increased A_2AR levels within the proposed PD animal model remains to be further investigated.

The adenosine A_2A receptor (A_2AR) has emerged as a potential non-dopaminergic target for the treatment of Parkinson’s disease and, thus, the non-invasive imaging with positron emission tomography (PET) is of utmost importance to monitor the receptor expression and occupancy during an A_2AR-tailored therapy. Aiming at the development of a PET radiotracer, we herein report the design of a series of novel fluorinated analogs (TOZ1-TOZ7) based on the structure of the A_2AR antagonist tozadenant, and the preclinical evaluation of [¹⁸F]TOZ1. Autoradiography proved A_2AR-specific in vitro binding of [¹⁸F]TOZ1 to striatum of mouse and pig brain. Investigations of the metabolic stability in mice revealed parent fractions of more than 76% and 92% of total activity in plasma and brain samples, respectively. Dynamic PET/magnetic resonance imaging (MRI) studies in mice revealed a brain uptake but no A_2AR-specific in vivo binding.