Alterations in gene regulation following inhibition of the striatum-enriched phosphodiesterase, PDE10A

Strick, Christine A.; James, Larry C.; Fox, Carol B.; Seeger, Thomas; Menniti, Frank S.; Schmidt, Christopher J.

doi:10.1016/j.neuropharm.2009.09.008

Cited by 50 publications

(58 citation statements)

References 46 publications

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“…In this study we confirm and extend the findings by Strick et al (2009), who showed that inhibition of PDE10A induced expression of c-fos in the striatum, and Piccart et al, 2011, who demonstrated that basal levels of egr-1 are elevated in the striatum of PDE10A-deficient mice. Overall, we demonstrate that the pattern of IEG expression in the striatum induced by MP-10 was similar for the IEGs arc, c-fos and egr-1.…”

Section: Discussionsupporting

confidence: 91%

“…Interestingly, the responsiveness of egr-1 and arc to MP-10 administration were generally greater than that observed for c-fos. These findings follow in-line with other historical observations that c-fos has a higher activation threshold than egr-1 (Eftekhari et al, 2013;Strick et al, 2009;Piccart et al, 2011). There were more similarities between arc and egr-1 expression in terms of intensity, but egr-1 appeared to have a slightly broader distribution.…”

Section: Discussionsupporting

confidence: 91%

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The PDE10A inhibitor MP-10 and haloperidol produce distinct gene expression profiles in the striatum and influence cataleptic behavior in rodents

et al. 2015

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 91%

The PDE10A inhibitor MP-10 and haloperidol produce distinct gene expression profiles in the striatum and influence cataleptic behavior in rodents

et al. 2015

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“…PDE10A is therefore an attractive target for novel therapies for a variety of neurologic and psychiatric disorders that involve striatal function (9), including Parkinson disease (10), Huntington disease (11,12), schizophrenia (13,14), memory disorders (15), depression, and addiction (16). Animal models of Huntington disease have shown that PDE10A expression is an extremely sensitive marker of striatal neuron loss (12,17), and Parkinson disease models have been used to demonstrate possible roles of PDE10A in both the early motor symptoms and the late complications of Parkinson disease due to prominent PDE10A-dependent dysregulation of corticostriatal signaling (10,18).…”

mentioning

confidence: 99%

In Vivo Assessment and Dosimetry of 2 Novel PDE10A PET Radiotracers in Humans: ¹⁸F-MNI-659 and ¹⁸F-MNI-654

et al. 2014

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Phosphodiesterase (PDE) 10A is an enzyme involved in the regulation of cyclic adenosine monophosphate and cyclic guanosine monophosphate and is highly expressed in medium-sized spiny neurons of the striatum, making it an attractive target for novel therapies for a variety of neurologic and psychiatric disorders that involve striatal function. Potential ligands for PET imaging of PDE10A have been reported. Here, we report the first-in-human characterization of 2 new PDE10A radioligands, 2-(2-(3-(1-(2-fluoroethyl)-1H-indazol-6-yl)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-4-isopropoxyisoindoline-1,3-dione ( 18 F-MNI-654) and 2-(2-(3-(4-(2-fluoroethoxy)phenyl)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-4-isopropoxyisoindoline-1,3-dione ( 18 F-MNI-659), with the goal of selecting the best one for use in future studies interrogating pathophysiologic changes in neuropsychiatric disorders and aiding pharmaceutical development targeting PDE10A. Methods: Eleven healthy volunteers participated in this study ( 18 F-MNI-654 test-retest, 2 men; 18 F-MNI-659 test-retest, 4 men and 1 woman; 18 F-MNI-659 dosimetry, 2 men and 2 women). Brain PET images were acquired over 5.5 h for 18 F-MNI-654 and over 3.5 h for 18 F-MNI-659, and pharmacokinetic modeling with plasma-and reference-region (cerebellar cortex)-based methods was performed. Whole-body PET images were acquired over 6 h for 18 F-MNI-659 and radiation dosimetry estimated with OLINDA. Results: Both radiotracers were similarly metabolized, with about 20% of intact parent remaining at 120 min after injection. PET time-activity data demonstrated that 18 F-MNI-654 kinetics were much slower than 18 F-MNI-659 kinetics. For 18 F-MNI-659, there was good agreement between the Logan and simplified reference tissue models for nondisplaceable binding potential (BP ND ), supporting noninvasive quantification, with test-retest variability less than 10% and intraclass correlation greater than 0.9. The 18 F-MNI-659 effective dose was estimated at 0.024 mSv/MBq. Conclusion: PET imaging in the human brain with 2 novel PDE10A 18 F tracers is being reported. Noninvasive quantification of 18 F-MNI-659 with the simplified reference tissue model using the cerebellum as a reference is possible. In addition, 18 F-MNI-659 kinetics are fast enough for a good estimate of BP ND with 90 min of data, with values around 3.0 in the basal ganglia. Finally, 18 F-MNI-659 dosimetry is favorable and consistent with values reported for other PET radiotracers currently used in humans.

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“…dose. [52]. Of relevance to this outcome, marketed D2 antagonists produce a similar increase of immediate early genes, cFOS and NT [44].…”

Section: Mp-10mentioning

confidence: 88%

The Use of PDE10A and PDE9 Inhibitors for Treating Schizophrenia

Tuttle

Kormos

2014

Small Molecule Therapeutics for Schizophrenia

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Schizophrenia (Scz) is a chronic and debilitating neurological disorder that afflicts approximately 1% of the general population with an increased incidence within families. Signs of this disorder typically appear between the ages of 16-30 although rare cases of childhood (<13) onset exist. Diagnosis of scz requires symptoms that persist for a duration of 1 month over a 6-month time period. The broad spectrum of symptoms are typically split into three categories: positive, negative, and cognitive. Implicit within these categories is the difficulty for stand-alone treatment methods, suggesting a combination of pharmacological and psychological treatment strategies is needed to manage this disease. Furthermore, while current pharmaceuticals are moderately effective at managing positive symptoms, the severe side effects lower patient compliance. Additionally, drugs used to treat negative and cognitive symptoms only have modest benefits, at best. Due to these limitations, there is a clear need for novel pharmaceuticals that modulate dysfunctional neurological pathways in scz patients. As such, both academic and pharmaceutical researchers are focused on identifying enzymes that can attenuate neurological signaling in disease-relevant brain regions. Specifically, this chapter will provide an in-depth review of current drug discovery efforts focused on inhibiting phosphodiesterase 10 and 9 (PDE10A, PDE9A, respectively).

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Alterations in gene regulation following inhibition of the striatum-enriched phosphodiesterase, PDE10A

Cited by 50 publications

References 46 publications

The PDE10A inhibitor MP-10 and haloperidol produce distinct gene expression profiles in the striatum and influence cataleptic behavior in rodents

The PDE10A inhibitor MP-10 and haloperidol produce distinct gene expression profiles in the striatum and influence cataleptic behavior in rodents

In Vivo Assessment and Dosimetry of 2 Novel PDE10A PET Radiotracers in Humans: ¹⁸F-MNI-659 and ¹⁸F-MNI-654

The Use of PDE10A and PDE9 Inhibitors for Treating Schizophrenia

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Alterations in gene regulation following inhibition of the striatum-enriched phosphodiesterase, PDE10A

Cited by 50 publications

References 46 publications

The PDE10A inhibitor MP-10 and haloperidol produce distinct gene expression profiles in the striatum and influence cataleptic behavior in rodents

The PDE10A inhibitor MP-10 and haloperidol produce distinct gene expression profiles in the striatum and influence cataleptic behavior in rodents

In Vivo Assessment and Dosimetry of 2 Novel PDE10A PET Radiotracers in Humans: 18F-MNI-659 and 18F-MNI-654

The Use of PDE10A and PDE9 Inhibitors for Treating Schizophrenia

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Product

Resources

About

In Vivo Assessment and Dosimetry of 2 Novel PDE10A PET Radiotracers in Humans: ¹⁸F-MNI-659 and ¹⁸F-MNI-654