Examining dopamine D3 receptor occupancy by antipsychotic drugs via [3H]7-OH-DPAT ex vivo autoradiography and its cross-validation via c-fos immunohistochemistry in the rat brain

Davoodi, Nima; Riele, Paula te; Langlois, Xavier

doi:10.1016/j.ejphar.2014.06.011

Cited by 9 publications

(8 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The goal of this work was to assess the relative proportion of D3R binding of 18 F‐fallypride. Thus, in an effort to differentiate this D3R binding of 18 F‐fallypride, following sets of experiments were carried out: (1) In vitro autoradiographic studies with 18 F‐fallypride and competition with various D3R‐selective drugs, 7‐OH‐DPAT, D3R agonist (Davoodi et al, ), in the rat and rabbit brain and BP 897 and NGB 2904 in rat brain (Table ). (2) PET studies in rats with 18 F‐fallypride under baseline and D3R‐selective drug competition at different doses.…”

Section: Introductionmentioning

confidence: 99%

Dopamine D3 receptor binding of¹⁸F-fallypride: Evaluation usingin vitroandin vivoPET imaging studies

Mukherjee

Constantinescu

Hoang

et al. 2015

Synapse

View full text Add to dashboard Cite

Identification of dopamine D3 receptors (D3R) in vivo is important to understand several brain functions related to addiction. The goal of this work was to identify D3R binding of the dopamine D2 receptor (D2R)/D3R imaging agent, 18F-fallypride. Brain slices from male Sprague-Dawley rats (n=6) and New Zealand White rabbits (n=6) were incubated with 18F-fallypride and D3R selective agonist (R)-7-OH-DPAT (98-fold D3R selective). Rat slices were also treated with BP 897 (68-fold D3R selective partial agonist) and NGB 2904 (56-fold D3R selective antagonist). In vivo rat studies (n=6) were done on Inveon PET using 18–37 MBq 18F-fallypride and drug-induced displacement by (R)-7-OH-DPAT, BP 897 and NGB 2904. PET/CT imaging of wild type (WT, n=2) and D2R knock-out (KO, n=2) mice were carried out with 18F-fallypride. (R)-7-OH-DPAT displaced binding of 18F-fallypride, both in vitro and in vivo. In vitro, at 10 nM (R)-7-OH-DPAT, 18F-fallypride binding in the rat ventral striatum (VST) and dorsal striatum (DST) and rabbit nucleus accumbens were reduced by ~10–15%. At 10 µM (R)-7-OH-DPAT all regions in rat and rabbit were reduced by ≥85%. In vivo reductions for DST and VST before and after (R)-7-OH-DPAT were: low-dose (0.015mg/kg) DST −22%, VST −29%; high-dose (1.88 mg/kg) DST −58%, VST −77%, suggesting D3R/D2R displacement. BP 897 and NGB 2904 competed with 18F-fallypride in vitro, but unlike BP 897, NGB2904 did not displace 18F-fallypride in vivo. The D2R KO mice lacked 18F-fallypride binding in the DST. In summary, our findings suggest that up to 20% of 18F-fallypride may be bound to D3R sites in vivo.

show abstract

Section: Introductionmentioning

confidence: 99%

Dopamine D3 receptor binding of¹⁸F-fallypride: Evaluation usingin vitroandin vivoPET imaging studies

Mukherjee

Constantinescu

Hoang

et al. 2015

Synapse

View full text Add to dashboard Cite

show abstract

“…Blocking D2-receptors with haloperidol, however, did not affect LIA. It should be noted that haloperidol is not D2-receptor selective, but has also some affinity to D3-receptors (Davoodi et al, 2014). Given that D2-and D3-receptors may have opposing roles in LIA at the level of single brain areas (Fernandes et al, 2012); it cannot be ruled out that also at systemic levels D2-and D3-receptor effects cancelled each other out in the action of haloperidol.…”

Section: No Role Of D2-receptors In Liamentioning

confidence: 98%

Neuropharmacology of light-induced locomotor activation

et al. 2015

View full text Add to dashboard Cite

“…Excellent brain penetration and levels were obtained for all compounds studied. To prove mGlu 2 target engagement, an ex vivo occupancy assay in rat native tissue was set up . Site‐directed mutagenesis studies have shown that mGlu 2 NAMs and PAMs share multiple amino acid residues in their allosteric binding pocket which influence their activity, therefore suggesting a common binding site.…”

Section: Initial Mglu2 Nam Gtpγs Sar Study Of the Anilinementioning

confidence: 99%

“…To prove mGlu 2 target engagement, an ex vivo occupancy assay in rat native tissue was set up. [14] Site-directed mutagenesis studies have shown that mGlu 2 NAMs [15] and PAMs [16] share multiple amino acid residues in their allostericb inding pocket which influence their activity,t herefore suggesting ac ommon binding site. Based on this, the tritiated selective mGlu 2 positive allosteric modulator (PAM) ligand [ 3 H]JNJ-46281222 previously developed by our team, was used to conductt he ex vivo occupancy studies.…”

mentioning

confidence: 99%

1,3,5‐Trisubstituted Pyrazoles as Potent Negative Allosteric Modulators of the mGlu_2/3 Receptors

et al. 2017

View full text Add to dashboard Cite

The metabotropic glutamate subtype2 (mGlu 2 )r eceptor is ap resynaptic membrane receptor distributed widely in brain that providesf eedback inhibitory control of glutamate release. Inhibition of the mGlu 2 receptor function with an egative allosteric modulator (NAM) enhances activity-dependent glutamate release, which may be of therapeutic benefitf or the treatment of neurologicala nd psychiatric disorders. An attractive pyrazole hit was identified after ah igh-throughput screening (HTS) campaign. The evolution of this hit is describedb y structure-activity relationship (SAR) studies on specific parts of the molecule. From near micromolar potency we could obtain compounds with single-digit nanomolar activity in the mGlu 2 NAM GTPgSa ssay.I na ddition to SAR on in vitro potency, am ore detailed overview is given with as pecific set of compounds on the excellent agreement between in vitro potency, free brain concentration, and ex vivo mGlu 2 receptor occupancy.F inally,t oo btain improved drug-like compounds, plans for future research are suggested towardi ncreasing free brain concentration while maintaining high in vitro potency.Glutamate is considered the most important excitatory neurotransmitter in the vertebrate brain.I tt riggers and modulates synaptic activity by interacting on two differentf amilies of receptors:l igand-gated ion channels, known as ionotropic glutamate receptors (iGlu), and Gprotein-coupled glutamate receptors termed metabotropic glutamate (mGlu) receptors. [1] These mGlu receptors can be divided into three different groups based on their sequence homology,p harmacological profile, and preferential signal transductionp athway:g roup I( mGlu 1 and mGlu 5 ), group II (mGlu 2 and mGlu 3 ), and group III (mGlu 4 , mGlu 6 ,m Glu 7 ,a nd mGlu 8 ). [2] The mGlu 2 receptori se xpressed on presynaptic nerve terminals just outside the synaptic cleft where it reduces excitatory neurotransmission in an activity-dependentm anner due to its negativef eedback regulation on the release of glutamate into the synapse. [3] Experimental studies suggest that mGlu receptors play an important role in brain functions relatedtoinformation storage and plasticity and may hold the key to the longevity and stability of synaptic plasticity underlying long-termm emory.P articularly group II mGlu receptors have been associatedw ith regulation of cognitive processes,m ostly in cortico-cortical and/or hippocampal regions. An egative allosteric modulator (NAM) at mGlu 2/3 receptors has been shown to increasel ongterm potentiation (LTP) in the dentate gyrus of hippocampal slices in vitro. [4] This suggests af avorable influence on learning and memory,a sc onfirmed by effectso fs uch compounds on long-term recognition memory,w orking memory,c ognitive flexibility,s patial learningo rs ocial recognition memory in various paradigms that assess cognitive functioninr odents.Several chemotypes of negative allostericm odulators of the group II mGlu receptors have been described, mainly by researchersa tH offmann-La Roche, with di...

show abstract

Examining dopamine D3 receptor occupancy by antipsychotic drugs via [3H]7-OH-DPAT ex vivo autoradiography and its cross-validation via c-fos immunohistochemistry in the rat brain

Cited by 9 publications

References 29 publications

Dopamine D3 receptor binding of¹⁸F-fallypride: Evaluation usingin vitroandin vivoPET imaging studies

Dopamine D3 receptor binding of¹⁸F-fallypride: Evaluation usingin vitroandin vivoPET imaging studies

Neuropharmacology of light-induced locomotor activation

1,3,5‐Trisubstituted Pyrazoles as Potent Negative Allosteric Modulators of the mGlu_2/3 Receptors

Contact Info

Product

Resources

About

Examining dopamine D3 receptor occupancy by antipsychotic drugs via [3H]7-OH-DPAT ex vivo autoradiography and its cross-validation via c-fos immunohistochemistry in the rat brain

Cited by 9 publications

References 29 publications

Dopamine D3 receptor binding of18F-fallypride: Evaluation usingin vitroandin vivoPET imaging studies

Dopamine D3 receptor binding of18F-fallypride: Evaluation usingin vitroandin vivoPET imaging studies

Neuropharmacology of light-induced locomotor activation

1,3,5‐Trisubstituted Pyrazoles as Potent Negative Allosteric Modulators of the mGlu2/3 Receptors

Contact Info

Product

Resources

About

Dopamine D3 receptor binding of¹⁸F-fallypride: Evaluation usingin vitroandin vivoPET imaging studies

Dopamine D3 receptor binding of¹⁸F-fallypride: Evaluation usingin vitroandin vivoPET imaging studies

1,3,5‐Trisubstituted Pyrazoles as Potent Negative Allosteric Modulators of the mGlu_2/3 Receptors