Phosphodiesterase 10A PET Radioligand Development Program: From Pig to Human

Plisson, Christophe; Weinzimmer, David; Jakobsen, Steen; Natesan, Sridhar; Salinas, Cristian; Lin, Shu-fei; Labaree, David; Zheng, Ming-Qiang; Nabulsi, Nabeel; Marques, Tiago Reis; Kapur, Shitij; Kawanishi, Eiji; Saijo, Takeaki; Gunn, Roger N.; Carson, Richard E.; Rabiner, Eugenii A.

doi:10.2967/jnumed.113.131409

Cited by 53 publications

(44 citation statements)

References 16 publications

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“…[ 11 C]Lu AE92686 also shows higher brain signals than the radiotracer [ 11 C]IMA107 used by Marques et al , and excellent reproducibility, and thus might be more sensitive to detecting group differences. 17, 46 …”

Section: Discussionmentioning

confidence: 99%

Striatal phosphodiesterase 10A and medial prefrontal cortical thickness in patients with schizophrenia: a PET and MRI study

et al. 2017

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The enzyme phosphodiesterase 10A (PDE10A) is abundant in striatal medium spiny neurons and has been implicated in the pathophysiology of schizophrenia in animal models and is investigated as a possible new pharmacological treatment target. A reduction of prefrontal cortical thickness is common in schizophrenia, but how this relates to PDE10A expression is unknown. Our study aim was to compare, we believe for the first time, the striatal non-displaceable binding potential (BPND) of the new validated PDE10A ligand [11C]Lu AE92686 between patients with schizophrenia and healthy controls. Furthermore, we aimed to assess the correlation of PDE10A BPND to cortical thickness. Sixteen healthy male controls and 10 male patients with schizophrenia treated with clozapine, olanzapine or quetiapine were investigated with positron emission tomography (PET) and magnetic resonance imaging (MRI). Striatal binding potential (BPND) of [11C]Lu AE92686 was acquired through dynamic PET scans and cortical thickness by structural MRI. Clinical assessments of symptoms and cognitive function were performed and the antipsychotic dosage was recorded. Patients with schizophrenia had a significantly lower BPND of [11C]Lu AE92686 in striatum (P=0.003) than healthy controls. The striatal BPND significantly correlated to cortical thickness in the medial prefrontal cortex and superior frontal gyrus across patients with schizophrenia and healthy controls. No significant correlation was observed between the BPND for [11C]Lu AE92686 in striatum and age, schizophrenia symptoms, antipsychotic dosage, coffee consumption, smoking, duration of illness or cognitive function in the patients. In conclusion, PDE10A may be important for functioning in the striato-cortical interaction and in the pathophysiology of schizophrenia.

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Section: Discussionmentioning

confidence: 99%

Striatal phosphodiesterase 10A and medial prefrontal cortical thickness in patients with schizophrenia: a PET and MRI study

et al. 2017

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“…2B; Table 2). Although AMG 3807 showed slightly better properties as a tracer than its enantiomer AMG 3808, we selected racemic AMG 580 as a tracer candidate mainly for two reasons: (1) the in vitro and in vivo properties of AMG 580 met or exceeded the selection criteria; and (2) a rapid purification procedure could be developed after [ (Plisson et al, 2014). After a survey of the two available tracers at the time of this work, together with our previous work (Hwang et al, 2014), we sought a tracer that could be radiolabeled with fluorine-18 because of its longer half-life and was distinct in structure from MP10 and the MP10 analog JNJ42259152.…”

Section: Discussionmentioning

confidence: 99%

“…Positron emission tomography (PET) imaging is widely used to assess target occupancy and to establish a correlation between occupancy and efficacy, which helps to select dosage in the clinic and helps to interpret clinical outcomes (Passchier et al, 2002;Wong and Pomper, 2003). To this end, several PDE10A PET tracers have been developed by us and others, including [ (Celen et al, 2010) (Kehler et al, 2014) (Barret et al, 2014), and [ (Plisson et al, 2014). In the current study, we identified and characterized AMG 580 [1-(4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidin-1-yl)-2-fluoropropan-1-one], a novel PDE10A antagonist tracer with a distinct chemical structure compared with previously published tracers, which exhibits desirable tracer profiles, such as subnanomolar PDE10A binding affinity, optimal in vitro and in vivo kinetic properties, and selective tissue uptake.…”

Section: Abbreviationsmentioning

confidence: 99%

AMG 580: A Novel Small Molecule Phosphodiesterase 10A (PDE10A) Positron Emission Tomography Tracer

Chen

Lester-Zeiner

Shi

et al. 2014

J Pharmacol Exp Ther

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Phosphodiesterase 10A (PDE10A) inhibitors have therapeutic potential for the treatment of psychiatric and neurologic disorders, such as schizophrenia and Huntington's disease. One of the key requirements for successful central nervous system drug development is to demonstrate target coverage of therapeutic candidates in brain for lead optimization in the drug discovery phase and for assisting dose selection in clinical development. Therefore, we identified AMG 580 [1-(4-(3-(4-(1H-benzo[d] imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidin-1-yl)-2-fluoropropan-1-one], a novel, selective small-molecule antagonist with subnanomolar affinity for rat, primate, and human PDE10A. We showed that AMG 580 is suitable as a tracer for lead optimization to determine target coverage by novel PDE10A inhibitors using triple-stage quadrupole liquid chromatography-tandem mass spectrometry technology. [ 3 H]AMG 580 bound with high affinity in a specific and saturable manner to both striatal homogenates and brain slices from rats, baboons, and human in vitro. Moreover, [18 F]AMG 580 demonstrated prominent uptake by positron emission tomography in rats, suggesting that radiolabeled AMG 580 may be suitable for further development as a noninvasive radiotracer for target coverage measurements in clinical studies. These results indicate that AMG 580 is a potential imaging biomarker for mapping PDE10A distribution and ensuring target coverage by therapeutic PDE10A inhibitors in clinical studies.

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“…Besides measuring the enzyme levels under (patho)physiological conditions, a suitable PDE10A radioligand could be used to determine PDE10A occupancy of drugs. Up to now, several PDE10A radioligands have been developed, most labeled with 11 C, eg, [ 11 C]MP10, [ 11 C]IMA107 or [ 11 C]LuAE92686, and a few 18 F‐labeled (Figure ) such as [ 18 F]JNJ41510417 and the more suitable [ 18 F]JNJ42259152, already tested in humans . Furthermore, the 2‐(2‐(3‐aryl‐4‐oxo‐3,4‐dihydroquinazolin‐2‐yl)ethyl)isoindoline‐1,3‐diones [ 18 F]MNI654 and [ 18 F]MNI659 have been identified as potential PDE10A radioligands with [ 18 F]MNI659 investigated in humans, and recently the 1‐(4‐(3‐(4‐(1H‐benzo[d]imidazole‐2‐carbonyl)phenoxy)pyrazin‐2‐yl)piperidin‐1‐yl)‐2‐fluoropropan‐1‐one [ 18 F]AMG580 was developed and tested in nonhuman primates …”

Section: Introductionmentioning

confidence: 99%

Radiosynthesis and biological evaluation of the new PDE10A radioligand [¹⁸F]AQ28A

Wagner

Teodoro

Deuther‐Conrad

et al. 2016

Labelled Comp Radiopharmac

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Cyclic nucleotide phosphodiesterase 10A (PDE10A) regulates the level of the second messengers cAMP and cGMP in particular in brain regions assumed to be associated with neurodegenerative and psychiatric diseases. A better understanding of the pathophysiological role of the expression of PDE10A could be obtained by quantitative imaging of the enzyme by positron emission tomography (PET). Thus, in this study we developed, radiolabeled, and evaluated a new PDE10A radioligand, 8-bromo-1-(6-[ F]fluoropyridin-3-yl)-3,4-dimethylimidazo[1,5-a]quinoxaline ([ F]AQ28A). [ F]AQ28A was radiolabeled by both nucleophilic bromo-to-fluoro or nitro-to-fluoro exchange using K[ F]F-K -carbonate complex with different yields. Using the superior nitro precursor, we developed an automated synthesis on a Tracerlab FX F-N module and obtained [ F]AQ28A with high radiochemical yields (33 ± 6%) and specific activities (96-145 GBq·μmol ) for further evaluation. Initially, we investigated the binding of [ F]AQ28A to the brain of different species by autoradiography and observed the highest density of binding sites in striatum, the brain region with the highest PDE10A expression. Subsequent dynamic PET studies in mice revealed a region-specific accumulation of [ F]AQ28A in this region, which could be blocked by preinjection of the selective PDE10A ligand MP-10. In conclusion, the data suggest [ F]AQ28A is a suitable candidate for imaging of PDE10A in rodent brain by PET.

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Phosphodiesterase 10A PET Radioligand Development Program: From Pig to Human

Cited by 53 publications

References 16 publications

Striatal phosphodiesterase 10A and medial prefrontal cortical thickness in patients with schizophrenia: a PET and MRI study

Striatal phosphodiesterase 10A and medial prefrontal cortical thickness in patients with schizophrenia: a PET and MRI study

AMG 580: A Novel Small Molecule Phosphodiesterase 10A (PDE10A) Positron Emission Tomography Tracer

Radiosynthesis and biological evaluation of the new PDE10A radioligand [¹⁸F]AQ28A

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Phosphodiesterase 10A PET Radioligand Development Program: From Pig to Human

Cited by 53 publications

References 16 publications

Striatal phosphodiesterase 10A and medial prefrontal cortical thickness in patients with schizophrenia: a PET and MRI study

Striatal phosphodiesterase 10A and medial prefrontal cortical thickness in patients with schizophrenia: a PET and MRI study

AMG 580: A Novel Small Molecule Phosphodiesterase 10A (PDE10A) Positron Emission Tomography Tracer

Radiosynthesis and biological evaluation of the new PDE10A radioligand [18F]AQ28A

Contact Info

Product

Resources

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Radiosynthesis and biological evaluation of the new PDE10A radioligand [¹⁸F]AQ28A