The ¹⁸F-labeling of CF₂H groups has been recently studied in radiopharmaceutical chemistry owing to the favorable nuclear and physical characteristics of the radioisotope ¹⁸F for positron emission tomography (PET). Following up on the reported efficiency of the [¹⁸F]difluoromethyl benzothiazolyl-sulfone ([¹⁸F]1) as a ¹⁸F-difluoromethylating reagent, we investigated the influence of structurally-related [¹⁸F]difluoromethyl heteroaryl-sulfones in the reactivity toward the photoredox C–H ¹⁸F-difluoromethylation of heteroarenes under continuous-flow conditions. In the present work, six new [¹⁸F]difluoromethyl heteroaryl-sulfones [¹⁸F]5a–[¹⁸F]5f were prepared and, based on the overall radiochemical yields (RCYs), three of these reagents ([¹⁸F]5a, [¹⁸F]5c, and [¹⁸F]5f) were selected for the fully automated radiosynthesis on a FASTlab^TM synthesizer (GE Healthcare) at high level of starting radioactivity. Subsequently, their efficiency as ¹⁸F-difluoromethylating reagents was evaluated using the antiherpetic drug acyclovir as a model substrate. Our results showed that the introduction of molecular modifications in the structure of [¹⁸F]1 influenced the amount of fac-Ir^III(ppy)₃ and the residence time needed to ensure a complete C–H ¹⁸F-difluoromethylation process. The photocatalytic C–H ¹⁸F-difluoromethylation reaction with the reagents [¹⁸F]5a, [¹⁸F]5c, and [¹⁸F]5f was extended to other heteroarenes. Radical-trapping experiments demonstrated the likely involvement of radical species in the C–H ¹⁸F-difluoromethylation process.

The synaptic vesicle protein 2 (SV2) is involved in synaptic vesicle trafficking. The SV2A isoform is the most studied and its implication in epilepsy therapy led to the development of the first SV2A PET radiotracer [¹⁸F]UCB-H. The objective of this study was to evaluate in vivo, using microPET in rats, the specificity of [¹⁸F]UCB-H for SV2 isoform A in comparison with the other two isoforms (B and C) through a blocking assay. Twenty Sprague Dawley rats were pre-treated either with the vehicle, or with specific competitors against SV2A (levetiracetam), SV2B (UCB5203) and SV2C (UCB0949). The distribution volume (Vt, Logan plot, t* 15 min) was obtained with a population-based input function. The Vt analysis for the entire brain showed statistically significant differences between the levetiracetam group and the other groups (p < 0.001), but also between the vehicle and the SV2B group (p < 0.05). An in-depth Vt analysis conducted for eight relevant brain structures confirmed the statistically significant differences between the levetiracetam group and the other groups (p < 0.001) and highlighted the superior and the inferior colliculi along with the cortex as regions also displaying statistically significant differences between the vehicle and SV2B groups (p < 0.05). These results emphasize the in vivo specificity of [¹⁸F]UCB-H for SV2A against SV2B and SV2C, confirming that [¹⁸F]UCB-H is a suitable radiotracer for in vivo imaging of the SV2A proteins with PET.

Nonspecific binding (NSB) is a key parameter in optimizing PET imaging tracers. We compared the ability to predict NSB of three available methods: LIMBA, rat f_u,brain, and CHI(IAM). Even though NSB is often associated with lipophilicity, we observed that logD does not correlate with any of these assays, clearly indicating that lipophilicity, while influencing NSB, is insufficient to predict it. A cross‐comparison of the methods showed that all three correlate and are useful predictors of NSB. The three assays, however, rank the molecules slightly differently, illustrating the challenge of comparing molecules within a narrow chemical space. We also noted that CHI(IAM) values more effectively predict V_NS, a measure of in vivo NSB in the human brain. CHI(IAM) measurements might be a closer model of the actual physicochemical interaction between PET tracer candidates and cell membranes, and seems to be the method of choice for the optimization of in vivo NSB.

The Cover Feature shows the two possible fates of a positron emission tomography (PET) imaging agent approaching its target: a nonspecific interaction with the membranes, or specific binding to the target protein. Quantifying and reducing the nonspecific binding of imaging agents during their chemical optimization is critical to ensure image quality. We show that the chromatographic hydrophilicity index on immobilized artificial membranes CHI(IAM) is the most effective method to predict V_NS, a direct measure of nonspecific binding in the living human brain. More information can be found in the Full Paper by Yves Auberson, Luca Gobbi, Joël Mercier, Benny Bang‐Andersen et al..