The chemistry of labeling heterocycles with carbon-11 or fluorine-18 for biomedical imaging

et al. 2023

J. Med. Chem.

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A positron emission tomography (PET) radioligand for imaging phosphodiesterase 4D (PDE4D) would benefit drug discovery and the investigation of neuropsychiatric disorders. The most promising radioligand to date, namely, [11C]T1650, has shown unstable quantification in humans. Structural elaboration of [11C]T1650 was therefore deemed necessary. High target affinity in the low nM range is usually required for successful PET radioligands. In our PDE4D PET radioligand development, we formulated and optimized an empirical equation (log[IC50 (nM)] = P1 + P2 + P3 + P4) that well described the relationship between binding affinity and empirically derived values (P1–P4) for the individual fragments in four subregions commonly composing each inhibitor (R 2 = 0.988, n = 62). This equation was used to predict compounds that would have high inhibitory potency. Fourteen new compounds were obtained with IC50 of 0.3–10 nM. Finally, eight compounds were judged to be worthy of future radiolabeling and evaluation as PDE4D PET radioligands.

Section: ■ Results and Discussionmentioning

confidence: 99%

An Empirical Quantitative Structure-Activity Relationship Equation Assists the Discovery of High-Affinity Phosphodiesterase 4D Inhibitors as Leads to PET Radioligands

Jiang

et al. 2023

J. Med. Chem.

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“…Radiocarbonylation reactions are an important complement to radiomethylation reactions because they considerably broaden the range of chemotypes that can be labeled as prospective PET radiotracers. It is therefore important to develop reliable and high‐yielding radiocarbonylation methods …”

Section: Methodsmentioning

confidence: 99%

“…It is therefore important to develop reliable and high-yielding radiocarbonylation methods. [3][4][5] [ 11 C]Phosgene ([ 11 C]COCl 2 ) fulfills a requirement for high reactivity in a labeling synthon for producing [carbonyl- 11 C]compounds (Scheme 1 A). However, [ 11 C]COCl 2 synthesis requires hazardous chlorine gas as well as complicated equipment that may need extensive maintenance and replacement of key components after each use.…”

mentioning

confidence: 99%

[¹¹C]Carbonyl Difluoride—a New and Highly Efficient [¹¹C]Carbonyl Group Transfer Agent

Jakobsson

et al. 2020

Angewandte Chemie

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Herein, the synthesis and use of [11C]carbonyl difluoride for labeling heterocycles with [11C]carbonyl groups in high molar activity is described. A very mild single‐pass gas‐phase conversion of [11C]carbon monoxide into [11C]carbonyl difluoride over silver(II) fluoride provides easy access to this new synthon in robust quantitative yield for labeling a broad range of cyclic substrates, for example, imidazolidin‐2‐ones, thiazolidin‐2‐ones, and oxazolidin‐2‐ones. Labeling reactions may utilize close‐to‐stoichiometric precursor quantities and short reaction times at room temperature in a wide range of solvents while also showing high water tolerability. The overall radiosynthesis protocol is both simple and reproducible. The required apparatus can be constructed from widely available parts and is therefore well suited to be automated for PET radiotracer production. We foresee that this straightforward method will gain wide acceptance for PET radiotracer syntheses across the radiochemistry community.

mentioning

confidence: 99%

[¹¹C]Carbonyl Difluoride—a New and Highly Efficient [¹¹C]Carbonyl Group Transfer Agent

Jakobsson

et al. 2020

Angew Chem Int Ed

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Herein, the synthesis and use of [ 11 C]carbonyl difluoride for labeling heterocycles with [ 11 C]carbonyl groups in high molar activity is described. A very mild single-pass gasphase conversion of [ 11 C]carbon monoxide into [ 11 C]carbonyl difluoride over silver(II) fluoride provides easy access to this new synthon in robust quantitative yield for labeling a broad range of cyclic substrates, for example, imidazolidin-2-ones, thiazolidin-2-ones, and oxazolidin-2-ones. Labeling reactions may utilize close-to-stoichiometric precursor quantities and short reaction times at room temperature in a wide range of solvents while also showing high water tolerability. The overall radiosynthesis protocol is both simple and reproducible. The required apparatus can be constructed from widely available parts and is therefore well suited to be automated for PET radiotracer production. We foresee that this straightforward method will gain wide acceptance for PET radiotracer syntheses across the radiochemistry community.Supporting information and the ORCID identification number(s) for the author(s) of this article can be found under: https://doi.