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44 pages, 8881 KiB

Open AccessReview

Challenges on Cyclic Nucleotide Phosphodiesterases Imaging with Positron Emission Tomography: Novel Radioligands and (Pre-)Clinical Insights since 2016

by Susann Schröder, Matthias Scheunemann, Barbara Wenzel and Peter Brust

Int. J. Mol. Sci. 2021, 22(8), 3832; https://doi.org/10.3390/ijms22083832 - 7 Apr 2021

Cited by 6 | Viewed by 3357

Abstract

Cyclic nucleotide phosphodiesterases (PDEs) represent one of the key targets in the research field of intracellular signaling related to the second messenger molecules cyclic adenosine monophosphate (cAMP) and/or cyclic guanosine monophosphate (cGMP). Hence, non-invasive imaging of this enzyme class by positron emission tomography (PET) using appropriate isoform-selective PDE radioligands is gaining importance. This methodology enables the in vivo diagnosis and staging of numerous diseases associated with altered PDE density or activity in the periphery and the central nervous system as well as the translational evaluation of novel PDE inhibitors as therapeutics. In this follow-up review, we summarize the efforts in the development of novel PDE radioligands and highlight (pre-)clinical insights from PET studies using already known PDE radioligands since 2016. Full article

(This article belongs to the Special Issue Role of Phosphodiesterase in Biology and Pathology)

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17 pages, 4893 KiB

Open AccessArticle

Radiosynthesis and Biological Investigation of a Novel Fluorine-18 Labeled Benzoimidazotriazine-Based Radioligand for the Imaging of Phosphodiesterase 2A with Positron Emission Tomography

by Rien Ritawidya, Barbara Wenzel, Rodrigo Teodoro, Magali Toussaint, Mathias Kranz, Winnie Deuther-Conrad, Sladjana Dukic-Stefanovic, Friedrich-Alexander Ludwig, Matthias Scheunemann and Peter Brust

Molecules 2019, 24(22), 4149; https://doi.org/10.3390/molecules24224149 - 15 Nov 2019

Cited by 5 | Viewed by 4234

Abstract

A specific radioligand for the imaging of cyclic nucleotide phosphodiesterase 2A (PDE2A) via positron emission tomography (PET) would be helpful for research on the physiology and disease-related changes in the expression of this enzyme in the brain. In this report, the radiosynthesis of a novel PDE2A radioligand and the subsequent biological evaluation were described. Our prospective compound 1-(2-chloro-5-methoxy phenyl)-8-(2-fluoropyridin-4-yl)-3- methylbenzo[e]imidazo[5,1-c][1,2,4]triazine, benzoimidazotriazine (BIT1) (IC₅₀ PDE2A = 3.33 nM; 16-fold selectivity over PDE10A) was fluorine-18 labeled via aromatic nucleophilic substitution of the corresponding nitro precursor using the K[¹⁸F]F-K_2.2.2-carbonate complex system. The new radioligand [¹⁸F]BIT1 was obtained with a high radiochemical yield (54 ± 2%, n = 3), a high radiochemical purity (≥99%), and high molar activities (155–175 GBq/μmol, n = 3). In vitro autoradiography on pig brain cryosections exhibited a heterogeneous spatial distribution of [¹⁸F]BIT1 corresponding to the known pattern of expression of PDE2A. The investigation of in vivo metabolism of [¹⁸F]BIT1 in a mouse revealed sufficient metabolic stability. PET studies in mouse exhibited a moderate brain uptake of [¹⁸F]BIT1 with a maximum standardized uptake value of ~0.7 at 5 min p.i. However, in vivo blocking studies revealed a non-target specific binding of [¹⁸F]BIT1. Therefore, further structural modifications are needed to improve target selectivity. Full article

(This article belongs to the Special Issue Radiolabelled Molecules for Brain Imaging with PET and SPECT)

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15 pages, 1301 KiB

Open AccessArticle

Investigation of an ¹⁸F-labelled Imidazopyridotriazine for Molecular Imaging of Cyclic Nucleotide Phosphodiesterase 2A

by Susann Schröder, Barbara Wenzel, Winnie Deuther-Conrad, Rodrigo Teodoro, Mathias Kranz, Matthias Scheunemann, Ute Egerland, Norbert Höfgen, Detlef Briel, Jörg Steinbach and Peter Brust

Molecules 2018, 23(3), 556; https://doi.org/10.3390/molecules23030556 - 2 Mar 2018

Cited by 8 | Viewed by 4957

Abstract

Specific radioligands for in vivo visualization and quantification of cyclic nucleotide phosphodiesterase 2A (PDE2A) by positron emission tomography (PET) are increasingly gaining interest in brain research. Herein we describe the synthesis, the ¹⁸F-labelling as well as the biological evaluation of our latest PDE2A (radio-)ligand 9-(5-Butoxy-2-fluorophenyl)-2-(2-([¹⁸F])fluoroethoxy)-7-methylimidazo[5,1-c]pyrido[2,3-e][1,2,4]triazine (([¹⁸F])TA5). It is the most potent PDE2A ligand out of our series of imidazopyridotriazine-based derivatives so far (IC₅₀ hPDE2A = 3.0 nM; IC₅₀ hPDE10A > 1000 nM). Radiolabelling was performed in a one-step procedure starting from the corresponding tosylate precursor. In vitro autoradiography on rat and pig brain slices displayed a homogenous and non-specific binding of the radioligand. Investigation of stability in vivo by reversed-phase HPLC (RP-HPLC) and micellar liquid chromatography (MLC) analyses of plasma and brain samples obtained from mice revealed a high fraction of one main radiometabolite. Hence, we concluded that [¹⁸F]TA5 is not appropriate for molecular imaging of PDE2A neither in vitro nor in vivo. Our ongoing work is focusing on further structurally modified compounds with enhanced metabolic stability. Full article

(This article belongs to the Special Issue Current Aspects of Radiopharmaceutical Chemistry)

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36 pages, 4347 KiB

Open AccessReview

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

by Susann Schröder, Barbara Wenzel, Winnie Deuther-Conrad, Matthias Scheunemann and Peter Brust

Molecules 2016, 21(5), 650; https://doi.org/10.3390/molecules21050650 - 19 May 2016

Cited by 22 | Viewed by 7064

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. Full article

(This article belongs to the Special Issue Molecular Imaging Probes)

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25 pages, 2462 KiB

Open AccessArticle

Synthesis, ¹⁸F-Radiolabelling and Biological Characterization of Novel Fluoroalkylated Triazine Derivatives for in Vivo Imaging of Phosphodiesterase 2A in Brain via Positron Emission Tomography

by Susann Schröder, Barbara Wenzel, Winnie Deuther-Conrad, Rodrigo Teodoro, Ute Egerland, Mathias Kranz, Matthias Scheunemann, Norbert Höfgen, Jörg Steinbach and Peter Brust

Molecules 2015, 20(6), 9591-9615; https://doi.org/10.3390/molecules20069591 - 26 May 2015

Cited by 16 | Viewed by 8613

Abstract

Phosphodiesterase 2A (PDE2A) is highly and specifically expressed in particular brain regions that are affected by neurological disorders and in certain tumors. Development of a specific PDE2A radioligand would enable molecular imaging of the PDE2A protein via positron emission tomography (PET). Herein we report on the syntheses of three novel fluoroalkylated triazine derivatives (TA2–4) and on the evaluation of their effect on the enzymatic activity of human PDE2A. The most potent PDE2A inhibitors were ¹⁸F-radiolabelled ([¹⁸F]TA3 and [¹⁸F]TA4) and investigated regarding their potential as PET radioligands for imaging of PDE2A in mouse brain. In vitro autoradiography on rat brain displayed region-specific distribution of [¹⁸F]TA3 and [¹⁸F]TA4, which is consistent with the expression pattern of PDE2A protein. Metabolism studies of both [¹⁸F]TA3 and [¹⁸F]TA4 in mice showed a significant accumulation of two major radiometabolites of each radioligand in brain as investigated by micellar radio-chromatography. Small-animal PET/MR studies in mice using [¹⁸F]TA3 revealed a constantly increasing uptake of activity in the non-target region cerebellum, which may be caused by the accumulation of brain penetrating radiometabolites. Hence, [¹⁸F]TA3 and [¹⁸F]TA4 are exclusively suitable for in vitro investigation of PDE2A. Nevertheless, further structural modification of these promising radioligands might result in metabolically stable derivatives. Full article

(This article belongs to the Special Issue Preparation of Radiopharmaceuticals and Their Use in Drug Development)

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20 pages, 1101 KiB

Open AccessArticle

Radiosynthesis and Radiotracer Properties of a 7-(2-[¹⁸F]Fluoroethoxy)-6-methoxypyrrolidinylquinazoline for Imaging of Phosphodiesterase 10A with PET

by Uta Funke, Winnie Deuther-Conrad, Gregor Schwan, Aurélie Maisonial, Matthias Scheunemann, Steffen Fischer, Achim Hiller, Detlef Briel and Peter Brust

Pharmaceuticals 2012, 5(2), 169-188; https://doi.org/10.3390/ph5020169 - 6 Feb 2012

Cited by 16 | Viewed by 8933

Abstract

Phosphodiesterase 10A (PDE10A) is a key enzyme of intracellular signal transduction which is involved in the regulation of neurotransmission. The molecular imaging of PDE10A by PET is expected to allow a better understanding of physiological and pathological processes related to PDE10A expression and function in the brain. The aim of this study was to develop a new ¹⁸F-labeled PDE10A ligand based on a 6,7-dimethoxy-4-pyrrolidinylquinazoline and to evaluate its properties in biodistribution studies. Nucleophilic substitution of the 7-tosyloxy-analogue led to the 7-[¹⁸F]fluoroethoxy-derivative [¹⁸F]IV with radiochemical yields of 25% ± 9% (n = 9), high radiochemical purity of ≥99% and specific activities of 110–1,100 GBq/μmol. [¹⁸F]IV showed moderate PDE10A affinity (K_D_,PDE10A = 14 nM) and high metabolic stability in the brain of female CD-1 mice, wherein the radioligand entered rapidly with a peak uptake of 2.3% ID/g in striatum at 5 min p.i. However, ex vivo autoradiographic and in vivo blocking studies revealed no target specific accumulation and demonstrated [¹⁸F]IV to be inapplicable for imaging PDE10A with PET. Full article

(This article belongs to the Special Issue Radiochemistry)

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