Radiosynthesis and Validation of 18F-FP-CMT, a Phenyltropane with Superior Properties for Imaging the Dopamine Transporter in Living Brain

To date there is no validated, 18F-labeled dopamine transporter (DAT) radiotracer with a rapid kinetic profile suitable for preclinical small-animal positron emission tomography (PET) studies in rodent models of human basal ganglia disease. Herein we report radiosynthesis and validation of the phenyltropane 18F-FP-CMT. Dynamic PET recordings were obtained for 18F-FP-CMT in six untreated rats, and six rats pretreated with the high-affinity DAT ligand GBR 12909; mean parametric maps of binding potential (BPND) relative to the cerebellum reference region, and maps of total distribution volume (VT) relative to the metabolite-corrected arterial input were produced. 18F-FP-CMT BPND maps showed peak values of ˜4 in the striatum, versus ˜0.4 in the vicinity of the substantia nigra. Successive truncation of the PET recordings indicated that stable BPND estimates could be obtained with recordings lasting only 45 minutes, reflecting rapid kinetics of 18F-FP-CMT. Pretreatment with GBR 12909 reduced the striatal binding by 72% to 76%. High-performance liquid chromatography analysis revealed rapid metabolism of 18F-FP-CMT to a single, non-brain penetrant hydrophilic metabolite. Total distribution of volume calculated relative to the metabolite-corrected arterial input was 4.4 mL/g in the cerebellum. The pharmacological selectivity of 18F-FP-CMT, rapid kinetic profile, and lack of problematic metabolites constitute optimal properties for quantitation of DAT in rat, and may also predict applicability in human PET studies

Synthesis, Radiosynthesis and Biological Evaluation of Buprenorphine‐Derived Phenylazocarboxamides as Novel μ‐Opioid Receptor Ligands

Targeted structural modifications have led to a novel type of buprenorphine‐derived opioid receptor ligand displaying an improved selectivity profile for the μ‐OR subtype. On this basis, it is shown that phenylazocarboxamides may serve as useful bioisosteric replacements for the widely occurring cinnamide units, without loss of OR binding affinity or subtype selectivity. This study further includes functional experiments pointing to weak partial agonist properties of the novel μ‐OR ligands, as well as docking and metabolism experiments. Finally, the unique bifunctional character of phenylazocarboxylates, herein serving as precursors for the azocarboxamide subunit, was exploited to demonstrate the accessibility of an 18F‐fluorinated analogue

Erratum: SC83288 is a clinical development candidate for the treatment of severe malaria

No abstract available

Erratum: SC83288 is a clinical development candidate for the treatment of severe malaria

No abstract available

[18F]Fluorophenylazocarboxylates: Design and Synthesis of Potential Radioligands for Dopamine D3 and μ-Opioid Receptor

18F-Labeled building blocks from the type of [18F]fluorophenylazocarboxylic-tert-butyl esters offer a rapid, mild, and reliable method for the 18F-fluoroarylation of biomolecules. Two series of azocarboxamides were synthesized as potential radioligands for dopamine D3 and the μ-opioid receptor, revealing compounds 3d and 3e with single-digit and sub-nanomolar affinity for the D3 receptor and compound 4c with only micromolar affinity for the μ-opioid receptor, but enhanced selectivity for the μ-subtype in comparison to the lead compound AH-7921. A “minimalist procedure” without the use of a cryptand and base for the preparation of 4-[18F]fluorophenylazocarboxylic-tert-butyl ester [18F]2a was established, together with the radiosynthesis of methyl-, methoxy-, and phenyl-substituted derivatives ([18F]2b–f). With the substituted [18F]fluorophenylazocarbylates in hand, two prototype azocarboxylates radioligands were synthesized by 18F-fluoroarylation, namely the methoxy azocarboxamide [18F]3d as the D3 receptor radioligand and [18F]4a as a prototype structure of the μ-opioid receptor radioligand. By introducing the new series of [18F]fluorophenylazocarboxylic-tert-butyl esters, the method of 18F-fluoroarylation was significantly expanded, thereby demonstrating the versatility of 18F-labeled phenylazocarboxylates for the design of potential radiotracers for positron emission tomography

Hydrogen Peroxide Promoted Mizoroki–Heck Reactions of Phenyldiazenes with Acrylates, Acrylamides, and Styrenes

Mizoroki–Heck reactions, which are well-known for aryldiazonium salts and which have recently been described for arylhydrazines, have now been extended to phenyldiazenes. In situ generation of phenyldiazenes from azocarboxylates allowed clean and selective reactions with styrenes, acrylates, and acrylamides using palladium­(II) acetate in the presence of silver­(I) acetate or hydrogen peroxide as oxidant. Hydrogen peroxide was thereby shown to be a cheap and broadly applicable alternative for the established palladium–silver­(I) system

[18F]Fluorophenylazocarboxylates: Design and Synthesis of Potential Radioligands for Dopamine D3 and μ-Opioid Receptor

18F-Labeled building blocks from the type of [18F]fluorophenylazocarboxylic-tert-butyl esters offer a rapid, mild, and reliable method for the 18F-fluoroarylation of biomolecules. Two series of azocarboxamides were synthesized as potential radioligands for dopamine D3 and the μ-opioid receptor, revealing compounds 3d and 3e with single-digit and sub-nanomolar affinity for the D3 receptor and compound 4c with only micromolar affinity for the μ-opioid receptor, but enhanced selectivity for the μ-subtype in comparison to the lead compound AH-7921. A “minimalist procedure” without the use of a cryptand and base for the preparation of 4-[18F]fluorophenylazocarboxylic-tert-butyl ester [18F]2a was established, together with the radiosynthesis of methyl-, methoxy-, and phenyl-substituted derivatives ([18F]2b–f). With the substituted [18F]fluorophenylazocarbylates in hand, two prototype azocarboxylates radioligands were synthesized by 18F-fluoroarylation, namely the methoxy azocarboxamide [18F]3d as the D3 receptor radioligand and [18F]4a as a prototype structure of the μ-opioid receptor radioligand. By introducing the new series of [18F]fluorophenylazocarboxylic-tert-butyl esters, the method of 18F-fluoroarylation was significantly expanded, thereby demonstrating the versatility of 18F-labeled phenylazocarboxylates for the design of potential radiotracers for positron emission tomography

[¹⁸F]Fluorophenylazocarboxylates: Design and Synthesis of Potential Radioligands for Dopamine D3 and μ‑Opioid Receptor

¹⁸F-Labeled building blocks from the type of [¹⁸F]­fluorophenylazocarboxylic-<i>tert</i>-butyl esters offer a rapid, mild, and reliable method for the ¹⁸F-fluoroarylation of biomolecules. Two series of azocarboxamides were synthesized as potential radioligands for dopamine D3 and the μ-opioid receptor, revealing compounds <b>3d</b> and <b>3e</b> with single-digit and sub-nanomolar affinity for the D3 receptor and compound <b>4c</b> with only micromolar affinity for the μ-opioid receptor, but enhanced selectivity for the μ-subtype in comparison to the lead compound AH-7921. A “minimalist procedure” without the use of a cryptand and base for the preparation of 4-[¹⁸F]­fluorophenylazocarboxylic-<i>tert</i>-butyl ester <b>[</b>^<b>18</b><b>F]­2a</b> was established, together with the radiosynthesis of methyl-, methoxy-, and phenyl-substituted derivatives (<b>[</b>^<b>18</b><b>F]­2b–f</b>). With the substituted [¹⁸F]­fluorophenylazocarbylates in hand, two prototype azocarboxylates radioligands were synthesized by ¹⁸F-fluoroarylation, namely the methoxy azocarboxamide <b>[</b>^<b>18</b><b>F]­3d</b> as the D3 receptor radioligand and <b>[</b>^<b>18</b><b>F]­4a</b> as a prototype structure of the μ-opioid receptor radioligand. By introducing the new series of [¹⁸F]­fluorophenylazocarboxylic-<i>tert</i>-butyl esters, the method of ¹⁸F-fluoroarylation was significantly expanded, thereby demonstrating the versatility of ¹⁸F-labeled phenylazocarboxylates for the design of potential radiotracers for positron emission tomography