Preclinical Evaluation of <sup>18</sup>F-PF-05270430, a Novel PET Radioligand for the Phosphodiesterase 2A Enzyme

Chen, Laigao; Nabulsi, Nabeel; Naganawa, Mika; Zasadny, Kenneth R.; Skaddan, Marc B.; Zhang, Lei; Najafzadeh, Soheila; Lin, Shu Fei; Helal, Christopher J.; Boyden, Tracey; Chang, Cheng; Ropchan, Jim; Carson, Richard E.; Villalobos, Anabella; Huang, Yiyun

doi:10.2967/jnumed.115.171454

Cited by 14 publications

(31 citation statements)

References 20 publications

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“…18 F-PF-05270430 was prepared as described in the companion paper (6) and in the supplemental materials (available at http://jnm. snmjournals.org).…”

Section: Radiotracer Synthesismentioning

confidence: 99%

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First-in-Human Assessment of the Novel PDE2A PET Radiotracer ¹⁸F-PF-05270430

et al. 2016

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This was a first-in-human study of the novel phosphodiesterase-2A (PDE2A) PET ligand 18 F-PF-05270430. The primary goals were to determine the appropriate tracer kinetic model to quantify brain uptake and to examine the within-subject test-retest variability. Methods: In advance of human studies, radiation dosimetry was determined in nonhuman primates. Six healthy male subjects participated in a testretest protocol with dynamic scans and metabolite-corrected input functions. Nine brain regions of interest were studied, including the striatum, white matter, neocortical regions, and cerebellum. Multiple modeling methods were applied to calculate volume of distribution (V T ) and binding potentials relative to the nondisplaceable tracer in tissue (BP ND ), concentration of tracer in plasma (BP P ), and free tracer in tissue (BP F ). The cerebellum was selected as a reference region to calculate binding potentials. Results: The dosimetry study provided an effective dose of less than 0.30 mSv/MBq, with the gallbladder as the critical organ; the human target dose was 185 MBq. There were no adverse events or clinically detectable pharmacologic effects reported. Tracer uptake was highest in the striatum, followed by neocortical regions and white matter, and lowest in the cerebellum. Regional time-activity curves were well fit by multilinear analysis-1, and a 70-min scan duration was sufficient to quantify V T and the binding potentials. BP ND , with mean values ranging from 0.3 to 0.8, showed the best intrasubject and intersubject variability and reliability. Testretest variability in the whole brain (excluding the cerebellum) of V T , BP ND , and BP P were 8%, 16%, and 17%, respectively. Conclusion: 18 F-PF-05270430 shows promise as a PDE2A PET ligand, albeit with low binding potential values.

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“…18 F-PF-05270430 was prepared as described in the companion paper (6) and in the supplemental materials (available at http://jnm. snmjournals.org).…”

Section: Radiotracer Synthesismentioning

confidence: 99%

“…The companion paper reports that the PET ligand 18 F-PF-05270430 is a potent inhibitor with high binding affinity for PDE2A (6). It shows excellent selectivity over other PDE subtypes and has good properties for PET imaging, as evaluated in nonhuman primates.…”

mentioning

confidence: 99%

First-in-Human Assessment of the Novel PDE2A PET Radiotracer ¹⁸F-PF-05270430

et al. 2016

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“…In NHP, brain distribution concordant with PDE2A expression was found, and occupancy studies in NHP with PDE2A inhibitor PF-05180999 showed a decrease in V T of 32% and a maximum BP ND reduction of 72%, in high-binding regions (Table 4) [127]. However, in lower uptake regions (including the cerebellum as the reference region), V T increased upon blocking, with no hypothesis from the authors discussed [127].…”

Section: Selectivity Data For 18 F-pf-05270430mentioning

confidence: 94%

“…[122] [126]. Large non-specific binding in NHP brain [127]. Presence of metabolites in rat brain, cerebellum activity increased upon blocking [127].…”

Section: Histone Deacetylasementioning

confidence: 99%

“…PDE2A is one of three isoforms of PDE2 and is highly expressed in limbic structures and basal ganglia of the brain and is concentrated in glutamate synapses [127]. Pre-clinical data has shown links to synaptic plasticity and cognition with PDE2A inhibitors having being investigated predominantly as treatments for schizophrenia and migraine, but they are also of interest in degenerative diseases [279][280][281].…”

Section: Pde2amentioning

confidence: 99%

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Advances in CNS PET: the state-of-the-art for new imaging targets for pathophysiology and drug development

McCluskey

Plisson

Rabiner

et al. 2019

Eur J Nucl Med Mol Imaging

102

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Purpose A limit on developing new treatments for a number of central nervous system (CNS) disorders has been the inadequate understanding of the in vivo pathophysiology underlying neurological and psychiatric disorders and the lack of in vivo tools to determine brain penetrance, target engagement, and relevant molecular activity of novel drugs. Molecular neuroimaging provides the tools to address this. This article aims to provide a state-of-the-art review of new PET tracers for CNS targets, focusing on developments in the last 5 years for targets recently available for inhuman imaging. Methods We provide an overview of the criteria used to evaluate PET tracers. We then used the National Institute of Mental Health Research Priorities list to identify the key CNS targets. We conducted a PubMed search (search period 1st of January 2013 to 31st of December 2018), which yielded 40 new PET tracers across 16 CNS targets which met our selectivity criteria. For each tracer, we summarised the evidence of its properties and potential for use in studies of CNS pathophysiology and drug evaluation, including its target selectivity and affinity, inter and intra-subject variability, and pharmacokinetic parameters. We also consider its potential limitations and missing characterisation data, but not specific applications in drug development. Where multiple tracers were present for a target, we provide a comparison of their properties. Results and conclusions Our review shows that multiple new tracers have been developed for proteinopathy targets, particularly tau, as well as the purinoceptor P2X7, phosphodiesterase enzyme PDE10A, and synaptic vesicle glycoprotein 2A (SV2A), amongst others. Some of the most promising of these include 18 F-MK-6240 for tau imaging, 11 C-UCB-J for imaging SV2A, 11 C-CURB and 11 C-MK-3168 for characterisation of fatty acid amide hydrolase, 18 F-FIMX for metabotropic glutamate receptor 1, and 18 F-MNI-444 for imaging adenosine 2A. Our review also identifies recurrent issues within the field. Many of the tracers discussed lack in vivo blocking data, reducing confidence in selectivity. Additionally, late-stage identification of substantial off-target sites for multiple tracers highlights incomplete preclinical characterisation prior to translation, as well as human disease state studies carried out without confirmation of test-retest reproducibility.

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Evaluation of advanced, pathophysiologic new targets for imaging of CNS

Singh

Srivastava

et al. 2023

Drug Development Research

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The inadequate information about the in vivo pathological, physiological, and neurological impairments, as well as the absence of in vivo tools for assessing brain penetrance and the efficiency of newly designed drugs, has hampered the development of new techniques for the treatment for variety of new central nervous system (CNS) diseases. The searching sites such as Science Direct and PubMed were used to find out the numerous distinct tracers across 16 CNS targets including tau, synaptic vesicle glycoprotein, the adenosine 2A receptor, the phosphodiesterase enzyme PDE10A, and the purinoceptor, among others. Among the most encouraging are [ 18 F]FIMX for mGluR imaging, [ 11 C]Martinostat for Histone deacetylase, [ 18 F]MNI-444 for adenosine 2A imaging, [ 11 C]ER176 for translocator protein, and [ 18 F]MK-6240 for tau imaging. We also reviewed the findings for each tracer's features and potential for application in CNS pathophysiology and therapeutic evaluation investigations, including target specificity, binding efficacy, and pharmacokinetic factors. This review aims to present a current evaluation of modern positron emission tomography tracers for CNS targets, with a focus on recent advances for targets that have newly emerged for imaging in humans.

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Preclinical Evaluation of ¹⁸F-PF-05270430, a Novel PET Radioligand for the Phosphodiesterase 2A Enzyme

Cited by 14 publications

References 20 publications

First-in-Human Assessment of the Novel PDE2A PET Radiotracer ¹⁸F-PF-05270430

First-in-Human Assessment of the Novel PDE2A PET Radiotracer ¹⁸F-PF-05270430

Advances in CNS PET: the state-of-the-art for new imaging targets for pathophysiology and drug development

Evaluation of advanced, pathophysiologic new targets for imaging of CNS

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Preclinical Evaluation of 18F-PF-05270430, a Novel PET Radioligand for the Phosphodiesterase 2A Enzyme

Cited by 14 publications

References 20 publications

First-in-Human Assessment of the Novel PDE2A PET Radiotracer 18F-PF-05270430

First-in-Human Assessment of the Novel PDE2A PET Radiotracer 18F-PF-05270430

Advances in CNS PET: the state-of-the-art for new imaging targets for pathophysiology and drug development

Evaluation of advanced, pathophysiologic new targets for imaging of CNS

Contact Info

Product

Resources

About

Preclinical Evaluation of ¹⁸F-PF-05270430, a Novel PET Radioligand for the Phosphodiesterase 2A Enzyme

First-in-Human Assessment of the Novel PDE2A PET Radiotracer ¹⁸F-PF-05270430

First-in-Human Assessment of the Novel PDE2A PET Radiotracer ¹⁸F-PF-05270430