We report a redox-neutral method for nucleophilic fluorination of N-hydroxyphthalimide esters using an Ir photocatalyst under visible light irradiation. The method provides access to a broad range of aliphatic fluorides, including primary, secondary, and tertiary benzylic fluorides as well as unactivated tertiary fluorides, that are typically inaccessible by nucleophilic fluorination due to competing elimination. In addition, we show that the decarboxylative fluorination conditions are readily adapted to radiofluorination with [ 18 F]KF. We propose that the reactions proceed by two electron transfers between the Ir catalyst and redox-active ester substrate to afford a carbocation intermediate that undergoes subsequent trapping by fluoride. Examples of trapping with O-and C-centered nucleophiles and deoxyfluorination via N-hydroxyphthalimidoyl oxalates are also presented, suggesting that this approach may offer a general blueprint for affecting redox-neutral SN1 substitutions under mild conditions. File list (2) download file view on ChemRxiv EWWJBP_JACSManuscript_Final.pdf (1.04 MiB) download file view on ChemRxiv Supporting Information.pdf (23.04 MiB)

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Radiocyanation is an attractive strategy for incorporating carbon-11 into radiotracer targets, particularly given the broad scope of acyl moieties accessible from nitriles. Most existing methods for aromatic radiocyanation require elevated temperatures (Cu-mediated reactions of aryl halides or organometallics) or involve expensive and toxic palladium complexes (Pd-mediated reactions of aryl halides). The current report discloses a complementary approach that leverages the capture of aryl radical intermediates by a Cu–11CN complex to achieve rapid and mild (5 min, room temperature) radiocyanation. In a first example, aryl radicals are generated via the reaction of a CuI mediator with an aryldiazonium salt (a Sandmeyer-type reaction) followed by radiocyanation with Cu–11CN. In a second example, aryl radicals are formed from aryl iodides via visible-light photocatalysis and then captured by a Cu–11CN species to achieve aryl–11CN coupling. This approach provides access to radiocyanated products that are challenging to access using other methods (e.g., ortho-disubstituted aryl nitriles).

Positron emission tomography (PET) is a highly sensitive and versatile molecular imaging modality that leverages radiolabeled molecules, known as radiotracers, to interrogate biochemical processes such as metabolism, enzymatic activity, and receptor expression. The ability to probe specific molecular and cellular events longitudinally in a noninvasive manner makes PET imaging a particularly powerful technique for studying the central nervous system (CNS) in both health and disease. Unfortunately, developing and translating a single CNS PET tracer for clinical use is typically an extremely resource-intensive endeavor, often requiring synthesis and evaluation of numerous candidate molecules. While existing in vitro methods are beginning to address the challenge of derisking molecules prior to costly in vivo PET studies, most require a significant investment of resources and possess substantial limitations. In the context of CNS drug development, significant time and resources have been invested into the development and optimization of computational methods, particularly involving machine learning, to streamline the design of better CNS therapeutics. However, analogous efforts developed and validated for CNS radiotracer design are conspicuously limited. In this Perspective, we overview the requirements and challenges of CNS PET tracer design, survey the most promising computational methods for in silico CNS drug design, and bridge these two areas by discussing the potential applications and impact of computational design tools in CNS radiotracer design.

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