Identification andin vivoevaluation of a fluorine-18 rolipram analogue, [¹⁸F]MNI-617, as a radioligand for PDE4 imaging in mammalian brain

Abstract

Phosphodiesterase (PDE) 4 is the most prevalent PDE in the central nervous system (CNS) and catalyzes hydrolysis of intracellular cAMP, a secondary messenger. By therapeutic inhibition of PDE4, intracellular cAMP levels can be stabilized, and the symptoms of psychiatric and neurodegenerative disorders including depression, memory loss and Parkinson's disease can be ameliorated. Radiotracers targeting PDE4 can be used to study PDE4 density and function, and evaluate new PDE4 therapeutics, in vivo in a non-invasive way, as has been shown using the carbon-11 labeled PDE4 inhibitor R-(-)-rolipram. Herein we describe a small series of rolipram analogs that contain fluoro- or iodo-substituents that could be used as fluorine-18 PET or iodine-123 SPECT PDE4 radiotracers. This series was evaluated with an in vitro binding assay and a 4-(fluoromethyl) derivative of rolipram, MNI-617, was identified, with a five-fold increase in affinity for PDE4 (Kd = 0.26 nM) over R-(-)-rolipram (Kd = 1.6 nM). A deutero-analogue d2 -[(18) F]MNI-617 was radiolabeled and produced in 23% yield with high (>5 Ci/µmol) specific activity and evaluated in non-human primate, where it rapidly entered the brain, with SUVs between 4 and 5, and with a distribution pattern consistent with that of PDE4.

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

“…Very recently, Thomae et al [82,83] reported on the development of structurally modified derivatives of ( R )- 6 with the aim to generate 18 F- and 123 I-labeled PDE4 radioligands for PET or SPECT application, respectively. In general, low tolerance of PDE4 for structural changes in ( R )- 6 has been stated as well as a significant decrease in PDE4 affinity for the iodo derivatives that consequently have been suggested to be not suitable as SPECT radioligands.…”

“…In general, low tolerance of PDE4 for structural changes in ( R )- 6 has been stated as well as a significant decrease in PDE4 affinity for the iodo derivatives that consequently have been suggested to be not suitable as SPECT radioligands. Out of this series, the fluorinated analogue 7 (MNI-617, Figure 2) has been described as the most promising compound with a five-fold increased PDE4 affinity over ( R )- 6 ( K D = 0.26 nM vs. 1.6 nM) and thus has been selected for 18 F-labeling [82,83].…”

“…Initially, [ 18 F] 7 has been prepared in an one-pot two-step radiosynthesis procedure via 18 F-labeling of diiodomethane using K + /[ 18 F]F − /K 2.2.2 -carbonate complex followed by O -alkylation of the corresponding phenol precursor with the resulting [ 18 F]fluoroiodomethane [82]. At the 21st International Symposium on Radiopharmaceutical Sciences, Columbia 2015, the group has presented an optimized two-step radiolabeling strategy by first generating [ 18 F]fluoromethane tosylate that has been used as a prosthetic group for subsequent O -alkylation of the phenol precursor under basic conditions (Scheme 4).…”

Fluorine-18 labelled building blocks for PET tracer synthesis

“…Radiochemical yields are comparable and range from 60 to 80% for the final alkylation step. 37,52,53 Analogous to the O-alkylation, aromatic S-alkylation of guanidine derivative 18 has been performed (Scheme 10). The reaction was carried out in MeCN at 110 1C for 15 minutes using cesium carbonate as base.…”

“…Reactions with [ 18 F]fluoromethyl tosylate. Scheme 9 O-Alkylated tracers with [ 18 F]fluoromethyl tosylate 37,52,53. Scheme 10 Synthesis of a S-fluoroalkyl guanidine derivative 54.…”