Publications by authors named "Maarten Ooms"

9 Publications

  • Page 1 of 1

Therapeutic Efficacy of Bi-labeled sdAbs in a Preclinical Model of Ovarian Cancer.

Mol Pharm 2020 09 13;17(9):3553-3566. Epub 2020 Aug 13.

In Vivo Cellular and Molecular Imaging Laboratory, Vrije Universiteit Brussel (VUB), 1090 Brussels, Belgium.

Targeted alpha-particle therapy (TAT) might be a relevant therapeutic strategy to circumvent resistance to conventional therapies in the case of HER2-positive metastatic cancer. Single-domain antibody fragments (sdAb) are promising vehicles for TAT because of their excellent properties, high target affinity, and fast clearance kinetics. This study combines the cytotoxic α-particle emitter bismuth-213 (Bi) and HER2-targeting sdAbs. The specificity, affinity, and cytotoxic potency of the radiolabeled complex were analyzed on HER2 cells. Its biodistribution through serial dissections and Cherenkov and micro-single-photon emission computed tomography (CT)/CT imaging was evaluated. Finally, the therapeutic efficacy and potential associated toxicity of [Bi]Bi-DTPA-2Rs15d were evaluated in a HER2 tumor model that manifests peritoneal metastasis. , [Bi]Bi-DTPA-2Rs15d bound HER2 cells in a HER2-specific way. In mice, high tumor uptake was reached already 15 min after injection, and extremely low uptake values were observed in normal tissues. Co-infusion of gelofusine resulted in a 2-fold reduction in kidney uptake. Administration of [Bi]Bi-DTPA-2Rs15d alone and in combination with trastuzumab resulted in a significant increase in median survival. We describe for the very first time the successful labeling of an HER2-sdAb with the α-emitter Bi, and after intravenous administration, revealing high stability and specific accumulation in target tissue and resulting in an increased median survival of these mice especially in combination with trastuzumab. These results indicate the potential of [Bi]Bi-DTPA-sdAb as a new radioconjugate for TAT, alone and as an add-on to trastuzumab for the treatment of HER2 metastatic cancer.
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http://dx.doi.org/10.1021/acs.molpharmaceut.0c00580DOI Listing
September 2020

Discovery, Radiolabeling, and Evaluation of Subtype-Selective Inhibitors for Positron Emission Tomography Imaging of Brain Phosphodiesterase-4D.

ACS Chem Neurosci 2020 05 8;11(9):1311-1323. Epub 2020 Apr 8.

National Institute of Mental Health, Bethesda, Maryland 20892-9663, United States.

We aimed to develop radioligands for PET imaging of brain phosphodiesterase subtype 4D (PDE4D), a potential target for developing cognition enhancing or antidepressive drugs. Exploration of several chemical series gave four leads with high PDE4D inhibitory potency and selectivity, optimal lipophilicity, and good brain uptake. These leads featured alkoxypyridinyl cores. They were successfully labeled with carbon-11 ( = 20.4 min) for evaluation with PET in monkey. Whereas two of these radioligands did not provide PDE4D-specific signal in monkey brain, two others, [C]T1660 and [C]T1650, provided sizable specific signal, as judged by pharmacological challenge using rolipram or a selective PDE4D inhibitor (BPN14770) and subsequent biomathematical analysis. Specific binding was highest in prefrontal cortex, temporal cortex, and hippocampus, regions that are important for cognitive function. [C]T1650 was progressed to evaluation in humans with PET, but the output measure of brain enzyme density () increased with scan duration. This instability over time suggests that radiometabolite(s) were accumulating in the brain. BPN14770 blocked PDE4D uptake in human brain after a single dose, but the percentage occupancy was difficult to estimate because of the unreliability of measuring . Overall, these results show that imaging of PDE4D in primate brain is feasible but that further radioligand refinement is needed, most likely to avoid problematic radiometabolites.
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http://dx.doi.org/10.1021/acschemneuro.0c00077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7444660PMC
May 2020

[C]()-Rolipram positron emission tomography detects DISC1 inhibition of phosphodiesterase type 4 in live locus-impaired mice.

J Cereb Blood Flow Metab 2019 07 12;39(7):1306-1313. Epub 2018 Feb 12.

1 Molecular Imaging Branch, NIMH, Bethesda, MD, USA.

Although still a matter of controversy, disrupted in schizophrenia protein 1 (DISC1) was suggested as a potential inhibitor of phosphodiesterase 4 (PDE4). We used locus impairment (LI) mice to investigate the interaction between PDE4 and DISC 1 and . [C]()-Rolipram binding was measured by PET in LI ( = 11) and C57BL/6 wild-type (WT,  = 9) mice. [C]()-Rolipram total distribution volumes () were calculated and corrected for plasma-free fraction () measured in a separate group of LI ( = 6) and WT ( = 7) mice. PDE4 enzyme activity was measured using samples of cerebral cortices from groups of LI ( = 4), heterozygote ( = 4), and WT ( = 4) mice. LI mice showed a 41% increase in (18 ± 6 vs. 13±4 mL/cm,  = 0.04) compared to WT mice. / showed a 73% significant increase (90 ± 31 vs. 52 ± 15 mL/cm,  = 0.004) in LI compared to WT mice. PDE4 enzymatic activity assay confirmed in vivo findings showing significant group differences ( < 0.0001). In conclusion, PDE4 activity was increased in the absence of critical DISC1 protein isoforms both in vivo and in vitro. Additionally, [C]()-Rolipram PET was sensitive enough to assess altered PDE4 activity caused by PDE4-DISC1 interaction.
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http://dx.doi.org/10.1177/0271678X18758997DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6668514PMC
July 2019

Synthesis and preclinical evaluation of [C]MA-PB-1 for in vivo imaging of brain monoacylglycerol lipase (MAGL).

Eur J Med Chem 2017 Aug 25;136:104-113. Epub 2017 Apr 25.

Laboratory for Radiopharmaceutical Research, Department of Pharmaceutical and Pharmacological Sciences, Campus Gasthuisberg O&N2, Herestraat 49 Box 821, BE-3000 Leuven, Belgium. Electronic address:

MAGL is a potential therapeutic target for oncological and psychiatric diseases. Our objective was to develop a PET tracer for in vivo quantification of MAGL. We report [C]MA-PB-1 as an irreversible MAGL inhibitor PET tracer. The in vitro inhibitory activity, ex vivo distribution, brain kinetics and specificity of [C]MA-PB-1 binding were studied. Ex vivo biodistribution and microPET showed good brain uptake which could be blocked by pretreatment with both MA-PB-1 and a structurally non-related MAGL inhibitor MJN110. These initial results suggest that [C]MA-PB-1 is a suitable tracer for in vivo imaging of MAGL.
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http://dx.doi.org/10.1016/j.ejmech.2017.04.066DOI Listing
August 2017

Striatal phosphodiesterase 10A availability is altered secondary to chronic changes in dopamine neurotransmission.

EJNMMI Radiopharm Chem 2017 21;1(1). Epub 2016 Mar 21.

Department of Pharmaceutical and Pharmacological Sciences KU Leuven, Laboratory for Radiopharmacy, Campus Gasthuisberg O&N 2, Herestraat 49 bus 821, 3000 Leuven, Belgium.

Background: Phosphodiesterase 10A (PDE10A) is an important regulator of nigrostriatal dopamine (DA) neurotransmission. However, little is known on the effect of alterations in DA neurotransmission on PDE10A availability. Here, we used [F]JNJ42259152 PET to measure changes in PDE10A availability, secondary to pharmacological alterations in DA release and to investigate whether these are D- or D-receptor driven.

Results: Acute treatment of rats using D-amphetamine (5 mg, s.c. and 1 mg/kg i.v.) did not result in a significant change in PDE10A BP compared to baseline conditions. 5-day D-amphetamine treatment (5 mg/kg, s.c.) increased striatal PDE10A BP compared to the baseline (+24 %,  = 0.03). Treatment with the selective D2 antagonist SCH23390 (1 mg/kg) and D-amphetamine decreased PDE10A binding (-22 %,  = 0.03). Treatment with only SCH23390 further decreased PDE10A binding (-26 %,  = 0.03). No significant alterations in PDE10A mRNA levels were observed.

Conclusions: Repeated D-amphetamine treatment significantly increased PDE10A binding, which is not observed upon selective D receptor blocking. This study suggests a potential pharmacological interaction between PDE10A enzymes and drugs modifying DA neurotransmission. Therefore, PDE10A binding in patients with neuropsychiatric disorders might be modulated by chronic DA-related treatment.
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http://dx.doi.org/10.1186/s41181-016-0005-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5843803PMC
March 2016

[18F]JNJ42259152 binding to phosphodiesterase 10A, a key regulator of medium spiny neuron excitability, is altered in the presence of cyclic AMP.

J Neurochem 2016 12 4;139(5):897-906. Epub 2016 Nov 4.

Laboratory for Radiopharmacy, Department of Pharmaceutical and Pharmacological Sciences KU Leuven, Leuven, Belgium.

Phosphodiesterase 10A (PDE10A) is a key regulator of medium spiny neuron excitability. Therefore, it plays an important role in the regulation of motor, reward, and cognitive processes. Despite the interest in PDE10A as a drug and positron emission tomography (PET) imaging target, little is known about the regulation of PDE10A enzymatic activity. This study aimed to further investigate the role of cAMP in the regulation of PDE10A activity and PDE10A PET imaging. Using [ F]JNJ42259152 as radioligand, we investigated alterations in PDE10A binding secondary to changes in cAMP levels. An in vitro striatum homogenate binding assay was developed to determine K and B of [ F]JNJ42259152. Homogenate binding was assessed after addition of increasing concentrations of exogenous cAMP (1, 10, and 100 μM). Rats were treated using JNJ49137530 and rolipram to induce in vivo alterations of cAMP. The effect of the induced cAMP alterations on PDE10A binding was assessed by comparing [ F]JNJ42259152 microPET studies after treatment to microPET studies acquired at baseline conditions prior to treatment. In vitro binding affinity of [ F]JNJ42259152 was higher in the presence of cAMP compared to baseline conditions (K  = 3.17 ± 0.91 nM with 10 μM cAMP vs. K  = 6.62 ± 0.7 nM at baseline). Inhibition of PDE4 using rolipram significantly increased [ F]JNJ42259152 binding (BP  = 2.61 ± 0.50 vs. 1.91 ± 0.36 at baseline). Administration of the PDE2 inhibitor JNJ49137530 significantly increased PDE10A binding potential (BP  = 2.74 ± 0.22 vs. 2.05 ± 0.16 at baseline). Our data indicate an important role for cAMP in the regulation of PDE10A activity. Additionally, our data show a profound interaction between several PDEs in striatum.
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http://dx.doi.org/10.1111/jnc.13855DOI Listing
December 2016

Retention of [(18)F]fluoride on reversed phase HPLC columns.

J Pharm Biomed Anal 2015 9;111:209-14. Epub 2015 Apr 9.

Laboratory for Radiopharmacy, Department of Pharmaceutical and Pharmacological Sciences KU Leuven, Leuven, Belgium. Electronic address:

As [(18)F]fluoride is a starting reagent in the radiosynthesis of most fluorine-18 labeled positron emission tomography (PET) tracers, its chromatographic behavior on reversed phase (RP) HPLC columns is important for the purification performance and accuracy of RP HPLC quality control methods. We have investigated the chromatographic behavior and recovery of [(18)F]fluoride as a function of the type and brand of RP HPLC column, the pH and the composition of the mobile phase. Elution and elution profile of [(18)F]fluoride from six RP-HPLC columns (Waters XBridge C18 3 mm × 100 mm 3.5 μm; Grace Platinum EPS C18 4.6 mm × 100 mm, 3 μm; Waters XTerra C18 4.6 mm × 250 mm, 5 μm; Phenomenex C18 4.6 mm × 150 mm, 5 μm; Hamilton PRP-1 column 4.1 mm × 150 mm, 5 μm; Merck KGaA Chromolith Performance C18 3 mm × 100 mm) eluted with mobile phase composed of phosphate or acetate buffers (pH 2, 3, 4, 5, 7.3 and 9) and acetonitrile or ethanol as organic modifier were characterized. The elution profile was determined by on-line radioactivity measurement in the column eluate and recovery was calculated by comparison of radioactivity eluted with the HPLC column present or absent in the chromatographic flow path. Interestingly, [(18)F]fluoride recovery increased with increasing pH. At pH 3 all packed silica-based columns showed significant retention of fluorine-18, whereas almost no retention was observed on a polymeric PRP-1 column. However at pH 5, [(18)F]fluoride recovery was above 90% for each tested column. In addition, small differences were observed when changing the composition of the mobile phase. We therefore recommend to use a mobile phase with pH > 5 for silica based C18 columns for both quality control and semi-preparative HPLC of fluorine-18 labeled PET radiopharmaceuticals. If required a lower pH can be used in combination with a polymer based HPLC column.
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http://dx.doi.org/10.1016/j.jpba.2015.04.009DOI Listing
February 2016

Early decrease of type 1 cannabinoid receptor binding and phosphodiesterase 10A activity in vivo in R6/2 Huntington mice.

Neurobiol Aging 2014 Dec 16;35(12):2858-2869. Epub 2014 Jun 16.

MoSAIC-Molecular Small Animal Imaging Centre, KU Leuven, Leuven, Belgium; Division of Nuclear Medicine, Department of Imaging and Pathology, KU Leuven and University Hospital Leuven, Leuven, Belgium. Electronic address:

Several lines of evidence imply early alterations in endocannabinoid and phosphodiesterase 10A (PDE10A) signaling in Huntington disease (HD). Using [(18)F]MK-9470 and [(18)F]JNJ42259152 small-animal positron emission tomography (PET), we investigated for the first time cerebral changes in type 1 cannabinoid (CB1) receptor binding and PDE10A levels in vivo in presymptomatic, early symptomatic, and late symptomatic HD (R6/2) mice, in relation to glucose metabolism ([(18)F]FDG PET), brain morphology (magnetic resonance imaging) and motor function. Ten R6/2 and 16 wild-type (WT) mice were investigated at 3 different time points between the age of 4 and 13 weeks. Parametric CB1 receptor and PDE10A images were anatomically standardized to Paxinos space and analyzed voxelwise. Volumetric microMRI imaging was performed to assess HD pathology. In R6/2 mice, CB1 receptor binding was decreased in comparison with WT in a cluster comprising the bilateral caudate-putamen, globus pallidus, and thalamic nucleus at week 5 (-8.1% ± 2.6%, p = 1.7 × 10(-5)). Longitudinal follow-up showed further progressive decline compared with controls in a cluster comprising the bilateral hippocampus, caudate-putamen, globus pallidus, superior colliculus, thalamic nucleus, and cerebellum (late vs. presymptomatic age: -13.7% ± 3.1% for R6/2 and +1.5% ± 4.0% for WT, p = 1.9 × 10(-5)). In R6/2 mice, PDE10A binding potential also decreased over time to reach significance at early and late symptomatic HD (late vs. presymptomatic age: -79.1% ± 1.9% for R6/2 and +2.1% ± 2.7% for WT, p = 1.5 × 10(-4)). The observed changes in CB1 receptor and PDE10A binding were correlated to anomalies exhibited by R6/2 animals in motor function, whereas no correlation was found with magnetic resonance imaging-based striatal volume. Our findings point to early regional dysfunctions in endocannabinoid and PDE10A signaling, involving the caudate-putamen and lateral globus pallidus, which may play a role in the progression of the disease in R6/2 animals. PET quantification of in vivo CB1 and/or PDE10A binding may thus be useful early biomarkers for HD. Our results also provide evidence of subtle motor deficits at earlier stages than previously described.
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http://dx.doi.org/10.1016/j.neurobiolaging.2014.06.010DOI Listing
December 2014

Synthesis and biological evaluation of carbon-11 and fluorine-18 labeled tracers for in vivo visualization of PDE10A.

Nucl Med Biol 2014 Sep 24;41(8):695-704. Epub 2014 May 24.

Laboratory for Radiopharmacy, KU Leuven, Belgium; MoSAIC, Molecular Small Animal Imaging Centre, KU Leuven, Belgium. Electronic address:

Introduction: In vivo visualization of PDE10A using PET provides a tool to evaluate the role of PDE10A in various neuropsychiatric diseases and can also be useful in the clinical evaluation of PDE10A inhibitor drug candidates. We evaluated several carbon-11 and fluorine-18 labeled PDE10A inhibitors as potential PDE10A PET radioligands.

Materials & Methods: [(11)C]MP10, [(11)C]JNJ42071965 and four other tracers were developed. Their biodistribution was evaluated in rats. Rat plasma and brain radiometabolites were quantified. Baseline microPET imaging was performed in normal rats and PDE10A knockout (KO) and wild-type (WT) mice. Blocking and displacement studies were conducted. The selectivity of the tracer binding was further studied in an ex vivo autoradiography experiment in PDE10A KO and WT mice.

Results: Biodistribution showed brain uptake for all tracers in the striatum and wash-out from the cerebellum. [(11)C]1 ((11)C-MP10) had the highest specific uptake index (striatum (S) vs. cerebellum (C) ratios (S/C)-1) at 60 min (7.4). [(11)C]5 ([(11)C]JNJ42071965) had a high index at the early time points (1.0 and 3.7 at 2 and 30 min p.i., respectively). The affinity of [(11)C]4, [(18)F]3 and [(18)F]6 was too low to visualize PDE10A using microPET. [(11)C] 2 showed a specific binding, while kinetics of [(11)C]1 were too slow. [(11)C]5 reached equilibrium after 10 min (uptake index=1.2). Blocking and displacement experiments in rats and baseline imaging in PDE10A KO mice showed specific and reversible binding of [(11)C]5 to PDE10A.

Conclusions: We successfully radiolabeled and evaluated six radiotracers for their potential to visualize PDE10A in vivo. While [(11)C]1 had the highest striatal specific uptake index, its slow kinetics likely compromise clinical use of this tracer. [(11)C]5 has a relatively high striatum-to-background ratio and fast kinetic profile, which makes it a valuable carbon-11 alternative.
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http://dx.doi.org/10.1016/j.nucmedbio.2014.05.138DOI Listing
September 2014