Preclinical evaluation of [18F]JNJ42259152 as a PET tracer for PDE10A

Celen, Sofie; Ooms, Maarten; Angelis, Meri De; Sannen, I.; Cornelis, Julie; Alcázar, Jesús; Schmidt, Mark E.; Verbruggen, Alfons; Langlois, Xavier; Laere, Koen Van; Andrés, Juvenal; Bormans, Guy

doi:10.1016/j.neuroimage.2013.04.123

Cited by 39 publications

(45 citation statements)

References 24 publications

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“…This relative fraction of unchanged [ 11 C]Lu AE92686 in plasma is dependent on the clearance rate of the radiometabolites in plasma, a rate which also may differ across species. However, in general, the potential difference in metabolic rate across species is consistent with less extensive metabolism in higher species, an observation previously reported for other radioligands [10, 11, 16, 17, 41]. …”

Section: Discussionsupporting

confidence: 86%

“…Shortening of the PET measurement duration has also been proposed for the application of other PDE10A radioligand, e.g. [ 18 F]JNJ-42259152 in rats, to overcome the confounding effects from BBB-penetrating radiometabolites [17]. Therefore, 63 min is suggested as the preferred PET measurement duration for [ 11 C]Lu AE92686 binding in cynomolgus monkeys.…”

Section: Discussionmentioning

confidence: 99%

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Characterization of [11C]Lu AE92686 as a PET radioligand for phosphodiesterase 10A in the nonhuman primate brain

Yang

Степанов

Amini

et al. 2016

Eur J Nucl Med Mol Imaging

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Purpose[11C]Lu AE92686 is a positron emission tomography (PET) radioligand that has recently been validated for examining phosphodiesterase 10A (PDE10A) in the human striatum. [11C]Lu AE92686 has high affinity for PDE10A (IC 50 = 0.39 nM) and may also be suitable for examination of the substantia nigra, a region with low density of PDE10A. Here, we report characterization of regional [11C]Lu AE92686 binding to PDE10A in the nonhuman primate (NHP) brain.MethodsA total of 11 PET measurements, seven baseline and four following pretreatment with unlabeled Lu AE92686 or the structurally unrelated PDE10A inhibitor MP-10, were performed in five NHPs using a high resolution research tomograph (HRRT). [11C]Lu AE92686 binding was quantified using a radiometabolite-corrected arterial input function and compartmental and graphical modeling approaches.ResultsRegional time-activity curves were best described with the two-tissue compartment model (2TCM). However, the distribution volume (V T) values for all regions were obtained by the Logan plot analysis, as reliable cerebellar V T values could not be derived by the 2TCM. For cerebellum, a proposed reference region, V T values increased by ∼30 % with increasing PET measurement duration from 63 to 123 min, while V T values in target regions remained stable. Both pretreatment drugs significantly decreased [11C]Lu AE92686 binding in target regions, while no significant effect on cerebellum was observed. Binding potential (BP ND) values, derived with the simplified reference tissue model (SRTM), were 13–17 in putamen and 3–5 in substantia nigra and correlated well to values from the Logan plot analysis.ConclusionsThe method proposed for quantification of [11C]Lu AE92686 binding in applied studies in NHP is based on 63 min PET data and SRTM with cerebellum as a reference region. The study supports that [11C]Lu AE92686 can be used for PET examinations of PDE10A binding also in substantia nigra.Electronic supplementary materialThe online version of this article (doi:10.1007/s00259-016-3544-9) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Characterization of [11C]Lu AE92686 as a PET radioligand for phosphodiesterase 10A in the nonhuman primate brain

Yang

Степанов

Amini

et al. 2016

Eur J Nucl Med Mol Imaging

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“…Furthermore, significant correlations were found between V T,M and V NS and between V NS and the fraction of metabolites in the arterial plasma compartment. Because there was evidence from preclinical experiments of a brain-penetrating radiometabolite in rodents (17), the current findings can be compatible also with a radiometabolite that is entering the brain, which could be a confounding factor for tracer quantification. Nevertheless, these findings also proved that both approaches were essentially the same and that metabolite kinetics could be modeled as nonspecific binding using only an intact tracer arterial input function.…”

Section: Discussionmentioning

confidence: 52%

“…Various radioligand binding experiments (including CEREP standard binding profiling) indicated that JNJ-42259152 at a concentration of 10 mM did not show affinity for most of the human receptors, ion channels, or transporters (Janssen Research and Development, unpublished data, 2011). In vivo blocking and displacement studies conducted in rats are the subject of a future preclinical evaluation study to be described elsewhere (17).…”

Section: Pharmacologic Properties Of Jnj-42259152mentioning

confidence: 99%

Quantification of ¹⁸F-JNJ-42259152, a Novel Phosphodiesterase 10A PET Tracer: Kinetic Modeling and Test–Retest Study in Human Brain

et al. 2013

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Phosphodiesterase 10A (PDE10A) plays a central role in striatal signaling and is implicated in several neuropsychiatric disorders, such as movement disorders and schizophrenia. We performed initial brain kinetic modeling of the novel PDE10A tracer 18 F-JNJ-42259152 (2-[[4-[1-(2-18 F-fluoroethyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]phenoxy]methyl]-3,5-dimethyl-pyridine) and studied test-retest reproducibility in healthy volunteers. Methods: Twelve healthy volunteers (5 men, 7 women; age range, 42-77 y) were scanned dynamically up to 135 min after bolus injection of 172.5 6 10.3 MBq of 18 F-JNJ42259152. Four volunteers (2 men, 2 women) underwent retest scanning, with a mean interscan interval of 37 d. Input functions and tracer parent fractions were determined using arterial sampling and high-performance liquid chromatography analysis. Volumes of interest for the putamen, caudate nucleus, ventral striatum, substantia nigra, thalamus, frontal cortex, and cerebellum were delineated using individual volumetric T1 MR imaging scans. Onetissue (1T) and 2-tissue (2T) models were evaluated to calculate total distribution volume (V T ). Simplified models were also tested to calculate binding potential (BP ND ), including the simplified reference tissue model (SRTM) and multilinear reference tissue model, using the frontal cortex as the optimal reference tissue. The stability of V T and BP ND was assessed down to a 60-min scan time. Results: The average intact tracer half-life in blood was 90 min. The 2T model V T values for the putamen, caudate nucleus, ventral striatum, substantia nigra, thalamus, frontal cortex, and cerebellum were 1.54 6 0.37, 0.90 6 0.24, 0.64 6 0.18, 0.42 6 0.09, 0.35 6 0.09, 0.30 6 0.07, and 0.36 6 0.12, respectively. The 1T model provided significantly lower V T values, which were well correlated to the 2T V T . SRTM BP ND values referenced to the frontal cortex were 3.45 6 0.43, 1.78 6 0.35, 1.10 6 0.31, and 0.44 6 0.09 for the respective target regions putamen, caudate nucleus, ventral striatum, and substantia nigra, with similar values for the multilinear reference tissue model. Good correlations were found for the target regions putamen, caudate nucleus, ventral striatum, and substantia nigra between the 2T-compartment model BP ND and the SRTM BP ND (r 5 0.57, 0.82, 0.70, and 0.64, respectively). SRTM BP ND using a 90-and 60-min acquisition interval showed low bias. Test-retest variability was 5%-19% for 2T V T and 5%-12% for BP ND SRTM. Conclusion: Kinetic modeling of 18 F-JNJ-42259152 shows that PDE10A activity can be reliably quantified and simplified using a reference tissue model with the frontal cortex as reference and a 60-min acquisition period.Key Words: PDE10A; PET; radioligand; 18 F; phosphodiesterase J Nucl Med 2013; 54:1285 54: -1293 54: DOI: 10.2967 Phosphodi esterase 10A (PDE10A) is a dual-substrate enzyme with a restricted distribution, predominantly in the human brain in medium spiny neurons of the striatum, the substantia nigra, the nucleus accumbens and olfactory tuberculum (1)...

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“…An improved radioligand, [ 18 F]-JNJ42259152 12, has recently been reported [66]. A thorough preclinical evaluation indicated this tracer binds specifically to PDE10A and has a good latency period.…”

Section: Pet Ligandsmentioning

confidence: 99%

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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Preclinical evaluation of [18F]JNJ42259152 as a PET tracer for PDE10A

Cited by 39 publications

References 24 publications

Characterization of [11C]Lu AE92686 as a PET radioligand for phosphodiesterase 10A in the nonhuman primate brain

Characterization of [11C]Lu AE92686 as a PET radioligand for phosphodiesterase 10A in the nonhuman primate brain

Quantification of ¹⁸F-JNJ-42259152, a Novel Phosphodiesterase 10A PET Tracer: Kinetic Modeling and Test–Retest Study in Human Brain

The Use of PDE10A and PDE9 Inhibitors for Treating Schizophrenia

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Preclinical evaluation of [18F]JNJ42259152 as a PET tracer for PDE10A

Cited by 39 publications

References 24 publications

Characterization of [11C]Lu AE92686 as a PET radioligand for phosphodiesterase 10A in the nonhuman primate brain

Characterization of [11C]Lu AE92686 as a PET radioligand for phosphodiesterase 10A in the nonhuman primate brain

Quantification of 18F-JNJ-42259152, a Novel Phosphodiesterase 10A PET Tracer: Kinetic Modeling and Test–Retest Study in Human Brain

The Use of PDE10A and PDE9 Inhibitors for Treating Schizophrenia

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Quantification of ¹⁸F-JNJ-42259152, a Novel Phosphodiesterase 10A PET Tracer: Kinetic Modeling and Test–Retest Study in Human Brain