Human biodistribution and dosimetry of 18F-JNJ42259152, a radioligand for phosphodiesterase 10A imaging

Laere, Koen Van; Ahmad, Rawaha; Hudyana, Hendra; Celen, Sofie; Dubois, Kristof; Schmidt, Mark E.; Bormans, Guy; Koole, Michel

doi:10.1007/s00259-012-2270-1

Cited by 32 publications

(27 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Time-integrated activity coefficients (formerly called residence times) were derived from the time-activity profiles. Individual organ doses and effective doses were determined using the OLINDA/EXM software (version 1.0; Vanderbilt University), with the same approach and curve-fitting procedures as applied previously (22).…”

Section: Discussionmentioning

confidence: 99%

¹¹C-MK-8278 PET as a Tool for Pharmacodynamic Brain Occupancy of Histamine 3 Receptor Inverse Agonists

et al. 2013

Self Cite

View full text Add to dashboard Cite

The histamine 3 (H3) receptor is a presynaptic autoreceptor in the central nervous system that regulates the synthesis and release of histamine and modulates the release of other major neurotransmitters. H3 receptor inverse agonists (IAs) may be efficacious in the treatment of various central nervous system disorders, including excessive daytime sleepiness, attention deficit hyperactivity disorder, Alzheimer disease, ethanol addiction, and obesity. Methods: Using PET and a novel high-affinity and selective radioligand 11 C-MK-8278, we studied the tracer biodistribution, quantification, and brain H3 receptor occupancy (RO) of MK-0249 and MK-3134, 2 potential IA drugs targeting cerebral H3 receptors, in 6 healthy male subjects (age, 19-40 y). The relationship among H3 IA dose, time on target, and peripheral pharmacokinetics was further investigated in 15 healthy male volunteers (age, 18-40 y) with up to 3 PET scans and 3 subjects per dose level. Results: The mean effective dose for 11 C-MK-8278 was 5.4 6 1.1 mSv/MBq. Human brain kinetics showed rapid high uptake and fast washout. Binding potential values can be assessed using the pons as a reference region, with a test-retest repeatability of 7%. Drug RO data showed low interindividual variability per dose (mean RO SD, 2.1%), and a targeted 90% RO can be reached for both IAs at clinically feasible doses. Conclusion: 11 C-MK-8278 is a useful novel PET radioligand for determination of human cerebral H3 receptor binding and allows highly reproducible in vivo brain occupancy of H3-targeting drugs, hereby enabling the evaluation of novel compounds in early development to select doses and schedules. Hi stamine is an aminergic neurotransmitter that is localized in the central nervous system (CNS) and in peripheral tissues such as the gut, skin, and immune system. In the brain, histaminergic neurons originate in the tuberomammillary nucleus of the hypothalamus and project throughout the CNS, including the thalamus, hypothalamus, cerebral cortex, striatum, medulla oblongata, and spinal cord. There are 4 known G-protein-coupled histamine receptor subtypes (H1-H4). These serve multiple functions in the brain, particularly control of excitability and plasticity. Type 1 and 2 histamine receptor-mediated actions are mostly excitatory. The H3 receptor was discovered in 1983 and cloned at the end of the twentieth century (1) and is mainly expressed in the CNS. H3 receptors predominate in the basal ganglia, with the highest densities in the globus pallidus (2). The H3 receptor is a presynaptic inhibitory autoreceptor that regulates the synthesis and release of histamine and also modulates the release of several other neurotransmitters such as acetylcholine, norepinephrine, serotonin, dopamine, and g aminobutyric acid. Like other G-protein-coupled receptors, H3 receptors signal constitutively, serving to tonically suppress histamine production at baseline. Agonist-induced signaling, such as that which occurs in the presence of elevated histamine levels, further suppresses histamine...

show abstract

Section: Discussionmentioning

confidence: 99%

¹¹C-MK-8278 PET as a Tool for Pharmacodynamic Brain Occupancy of Histamine 3 Receptor Inverse Agonists

et al. 2013

Self Cite

View full text Add to dashboard Cite

show abstract

“…In humans, a first-in-man biodistribution and dosimetry study showed that the tracer was safe and displayed promising kinetics for further quantitative evaluation of PDE10A activity in the nigrostriatal circuit (16).…”

Section: F-jnj-42259152 or 2-[[4-[1-(2-18 F-fluoroethyl)-4-(4-pyridimentioning

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

Self Cite

View full text Add to dashboard Cite

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)...

show abstract

“…Potential ligands for PET imaging of PDE10A have been reported (19)(20)(21)(22)(23)(24). Papaverine, a widely used inhibitor of PDE10A activity, lacked suitable imaging characteristics when 11 C-labeled (22).…”

mentioning

confidence: 99%

“…18 F-JNJ41510417 was demonstrated to have good pharmacologic and anatomic specificity in rodent PET studies (23) but had a radiometabolite entering the brain. More recently, human studies with 18 F-JNJ42259152 were reported (20,25).…”

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

View full text Add to dashboard Cite

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.

show abstract

Human biodistribution and dosimetry of 18F-JNJ42259152, a radioligand for phosphodiesterase 10A imaging

Abstract: In humans, (18)F-JNJ42259152 has an appropriate distribution, brain kinetics and safety. The estimated effective dose was within WHO class IIb with low interindividual variability. Therefore, the tracer is suitable for further kinetic evaluation in humans.

Cited by 32 publications

References 21 publications

¹¹C-MK-8278 PET as a Tool for Pharmacodynamic Brain Occupancy of Histamine 3 Receptor Inverse Agonists

¹¹C-MK-8278 PET as a Tool for Pharmacodynamic Brain Occupancy of Histamine 3 Receptor Inverse Agonists

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

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

Contact Info

Product

Resources

About

Human biodistribution and dosimetry of 18F-JNJ42259152, a radioligand for phosphodiesterase 10A imaging

Abstract: In humans, (18)F-JNJ42259152 has an appropriate distribution, brain kinetics and safety. The estimated effective dose was within WHO class IIb with low interindividual variability. Therefore, the tracer is suitable for further kinetic evaluation in humans.

Cited by 32 publications

References 21 publications

11C-MK-8278 PET as a Tool for Pharmacodynamic Brain Occupancy of Histamine 3 Receptor Inverse Agonists

11C-MK-8278 PET as a Tool for Pharmacodynamic Brain Occupancy of Histamine 3 Receptor Inverse Agonists

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

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

Contact Info

Product

Resources

About

¹¹C-MK-8278 PET as a Tool for Pharmacodynamic Brain Occupancy of Histamine 3 Receptor Inverse Agonists

¹¹C-MK-8278 PET as a Tool for Pharmacodynamic Brain Occupancy of Histamine 3 Receptor Inverse Agonists

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

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