Novel Radioligands for Cyclic Nucleotide Phosphodiesterase Imaging with Positron Emission Tomography: An Update on Developments Since 2012

Abstract

Cyclic nucleotide phosphodiesterases (PDEs) are a class of intracellular enzymes that inactivate the secondary messenger molecules, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Thus, PDEs regulate the signaling cascades mediated by these cyclic nucleotides and affect fundamental intracellular processes. Pharmacological inhibition of PDE activity is a promising strategy for treatment of several diseases. However, the role of the different PDEs in related pathologies is not completely clarified yet. PDE-specific radioligands enable non-invasive visualization and quantification of these enzymes by positron emission tomography (PET) in vivo and provide an important translational tool for elucidation of the relationship between altered expression of PDEs and pathophysiological effects as well as (pre-)clinical evaluation of novel PDE inhibitors developed as therapeutics. Herein we present an overview of novel PDE radioligands for PET published since 2012.

Keywords: PDE inhibitors; PDE radioligands; cyclic nucleotide signaling; imaging; phosphodiesterases; positron emission tomography.

Figure 1

Molecular structures of ¹⁸F-labeled PDE2A inhibitors for PET.

Scheme 1

Radiosynthesis of [¹⁸F]1.

Scheme 2

Radiosynthesis of [¹⁸F]2.

Scheme 3

Radiosyntheses of [¹⁸F]3, [¹⁸F]4, and [¹⁸F]5.

Figure 2

Molecular structures of PDE4 inhibitor (R)-6 and the ¹⁸F-analogue thereof for PET.

Scheme 4

Radiosynthesis of [¹⁸F]7.

Figure 3

Molecular structures of PDE5A inhibitors and ¹¹C- or ¹⁸F-labeled derivatives thereof for PET.

Scheme 5

Radiosyntheses of [¹¹C]12 and [¹⁸F]13.

Scheme 6

Radiosynthesis of [¹¹C]16.

Scheme 7

Molecular structure and radiosynthesis of [¹⁸F]18 as PDE5A radioligand for PET (TBAF = tetra-n-butylammonium fluoride).

Figure 4

Molecular structures of PDE7A/B inhibitor 19 and ¹⁸F- or ¹¹C-labeled derivatives thereof for PET.

Scheme 8

Radiosynthesis of [¹⁸F]20.

Scheme 9

Radiosynthesis of [¹¹C]21.

Figure 5

Molecular structures of PDE10A inhibitor 22 and ¹¹C- or ¹⁸F-labeled derivatives thereof for PET.

Figure 6

Molecular structures of further ¹¹C- or ¹⁸F-labeled derivatives of compound 22 as PDE10A radioligands for PET.

Scheme 10

Radiosynthesis of [¹¹C]30.

Scheme 11

Radiosyntheses of [¹⁸F]37 and [¹⁸F]40.

Figure 7

Molecular structures of PDE10A inhibitor 41 and the ¹¹C-labeled derivative thereof for PET.

Scheme 12

Radiosynthesis of [¹¹C]42.

Figure 8

Molecular structures of 43, a related PDE10A inhibitor and the ¹⁸F-labeled derivative thereof for PET.

Figure 9

Molecular structures of a PDE10A inhibitor and the ¹⁸F-labeled derivative thereof for PET.

Scheme 13

Radiosynthesis of [¹⁸F]47.

Figure 10

Molecular structures of ¹⁸F-labeled PDE10A radioligands for PET.

Scheme 14

Radiosynthesis of [¹⁸F]49.

Figure 11

Molecular structures of ¹¹C- or ¹⁸F-labeled PDE10A radioligands for PET.

Scheme 15

Radiosynthesis of [¹¹C]52 (TBAH = tetra-n-butylammonium hydroxide).

Scheme 16

Molecular structure and radiosynthesis of [¹¹C]54 as PDE10A radioligand for PET.

Figure 12

Molecular structures of ¹¹C- or ¹⁸F-labeled PDE10A radioligands for PET and the PDE10A inhibitor 57.

Scheme 17

Radiosynthesis of [¹¹C]55.

Scheme 18

Radiosynthesis of [¹⁸F]56.

Figure 13

Molecular structures of ¹¹C-labeled PDE10A radioligands for PET and the PDE10A inhibitor 65.

Scheme 19

Radiosynthesis of [¹¹C]61.

Figure 14

Molecular structures of ¹¹C-labeled PDE10A radioligands for PET and the PDE10A inhibitor 70.

Scheme 20

Radiosynthesis of [¹¹C]66.