Effects of antipsychotics on D3 receptors: A clinical PET study in first episode antipsychotic naive patients with schizophrenia using [11C]-(+)-PHNO

https://doi.org/10.1016/j.schres.2011.05.005Get rights and content

Abstract

Most antipsychotics are thought to have an effect on D2 and D3 receptors, although their D3, versus D2 binding has not been clearly established in vivo in humans. However, the development of [11C]-(+)-PHNO now permits the differentiation of antipsychotic activity on these two receptor subtypes. In this study we examined the effects of antipsychotics on D2 and D3 receptors by comparing [11C]-(+)-PHNO in D2-rich (caudate, CAU and putamen, PUT), mixed (ventral striatum) and D3-rich (globus-pallidus, GP and substantia nigra, SN) regions before and after the initiation of antipsychotic medication. The investigation therefore represents a longitudinal within-subject follow-up design wherein antipsychotic-naive patients with schizophrenia spectrum disorders were first scanned in a drug-naïve state and then again after ~ 2.5 weeks of antipsychotic treatment (risperidone or olanzapine). Binding potential (non displaceable or BPND) was obtained to derive estimates of drug occupancy in the identified brain regions.

Antipsychotic treatment was associated with the expected occupancies in the D2-rich regions; unexpectedly though, patients showed a higher, rather than the expected lower, [11C]-(+)-PHNO BPND in the GP and SN despite simultaneous evidence for ongoing D2 blockade in the other regions (CAU and PUT).

In conclusion, patients treated with atypical antipsychotics demonstrated no evidence of D3 receptor occupancy, but instead possible D3 up-regulation following short-term treatment. The present findings add to a very limited body of evidence related to D3 binding in vivo. [11C]-(+)-PHNO offer new opportunities for exploring the potential therapeutic significance of the D3 receptor in schizophrenia and the action of antipsychotics.

Introduction

Over five decades following their clinical introduction, we continue in our efforts to better understand the action of antipsychotic drugs. Clinical efficacy and side effects have been consistently related to in vivo D2 receptor occupancy (Farde et al., 1988, Kapur et al., 1995, Nordstrom et al., 1998, Kapur et al., 2000), and more recent neuroimaging data have identified that clinical response is optimized with D2 occupancy levels in the range of 60%, with the added caveat that side effects (i.e., parkinsonism) increase in frequency at levels > 80% (Kapur and Mamo, 2003). These studies have been performed with Positron Emission Tomography (PET) or Single Photon Emission Tomography (SPECT) radioligands which are antagonists for the dopamine D2/3 receptor: [11C]-raclopride, [11C]-FLB, [18F]-Fallypride or 123IBZM. However, since these radioligands have similar affinity for D2 and D3 receptors, it has been difficult to infer the precise involvement of each of these receptors, an important question that as of yet remains poorly understood.

[11C]-(+)-PHNO ([11C]-(+)-4-propyl-9-hydroxynaphthoxazine) is a D2/3 agonist radiotracer (Wilson et al., 2005) that binds with nanomolar affinity to D3 and D2 receptors, allowing for a prominent signal from the striatum and globus pallidus (GP) (Willeit et al., 2006). [11C]-(+)-PHNO demonstrates greater than ten-fold higher affinity for D3 versus D2 (Parker et al., 2006) in vitro, and an estimated ~ 20 fold in vivo (Gallezot et al., 2009a). This preferential binding to D3 has been confirmed ex vivo in rodents (Rabiner et al., 2009), and in vivo in non-human primates and humans (Narendran et al., 2006a, Rabiner et al., 2007a, Abi-Saab et al., 2008). While [11C]-(+)-PHNO binds preferentially to D3, the overall regional signal is a function of the differential affinity as well as concentration of D3versus D2 receptors in a given region. In D3-rich regions like the GP, D3 binding is thought to account for ~ 67% of the [11C]-(+)-PHNO signal, while the substantia nigra represents 100% D3 binding; thus, the signal in this region can isolate the D3 effects (Searle et al., 2010, Tziortzi et al., 2011). In other regions like the dorsal striatum, (caudate, CAU and putamen, and PUT), the relative concentration of D2 receptors is much higher and, therefore, only a small component of the signal, 10–40%, is attributable to D3 (Rabiner et al., 2007a, Abi-Saab et al., 2008). Consequently, the GP and SN can be used as a D3 preferential binding region while the dorsal striatum represents a D2 preferential region, and [11C]-(+)-PHNO provides an opportunity to study the differential effects of antipsychotics on D2versus D3 receptors by comparing CAU–PUT versus GP–SN in the same subject. Furthermore, the use of high resolution PET systems like the HRRT allows for better characterization of D3 binding given the small brain regions to examine.

Recently, a cross-sectional study in a large number of chronically treated patients with schizophrenia using [11C]-Raclopride and [11C]-(+)-PHNO showed relatively similar occupancies as measured by the two ligands in the caudate and putamen, but widely divergent and opposite results in the GP where no occupancy was found with [11C]-(+)-PHNO (Graff-Guerrero et al., 2009). This study also established that pramipexole, a D3 preferential agonist, displaced the unblocked binding in the GP, implicating D3. However, this study incorporated a cross-sectional uncontrolled-treatment design in patients chronically exposed to antipsychotics (mean duration = 9 years), thereby leaving an important questions unanswered. Are results similar in antipsychotic-naïve individuals free of the potential confound of chronic antipsychotic exposure? Further, what is the more immediate effect of antipsychotic exposure on D3 BPND, using the subject's antipsychotic-naïve state as the baseline measure for the purpose of comparison?

To answer these questions, we undertook a longitudinal study in patients with first episode schizophrenia, and scanned them in the HRRT scanning system in a drug-naïve state and following at least two weeks of ongoing antipsychotic treatment.

Section snippets

Clinical sample

This study was approved by the local Research Ethics Board at the Centre for Addiciton and Mental Health (CAMH) and University of Toronto. Patients were eligible to participate if they were: antipsychotic-naïve; met criteria for diagnosis of schizophrenia or schizoaffective disorder, as corroborated using the MINI-Plus structured interview (Sheehan et al., 1998); interested in starting antipsychotic medication (risperidone or olanzapine) and competent to provide written, informed consent.

Results

Eight first episode, antipsychotic-naive patients (male = 5; female = 3) with schizophrenia spectrum disorders (6 schizophrenia and 2 schizoaffective) and mean age of 33.0 ± 9 years, were included. All were antipsychotic-naïve at the study's initiation; 7 subjects were started on risperidone (mean dose 2.54 ± 0.11 mg) and one on olanzapine (dose 10 mg) at the clinical discretion of their treating psychiatrist and kept unchanged until the second PET scan (~ 2.5 weeks apart). Clinically, there was a

Discussion

Our results indicated no decrease in [11C]-(+)-PHNO binding in the GP and SN, a D3-rich region, following sub-chronic antipsychotic treatment, although the expected decrease was noted in the specified D2-rich region (CAU–PUT). These human in vivo data are remarkably consistent with recent ex-vivo experiments showing lack of blockade of the D3 receptor by risperidone, olanzapine and clozapine (McCormick et al., 2010). In fact, depending upon the method of analysis, there was an increase in [11

Role of funding source

This work was supported by the Canadian Institutes for Health Research (#157739 and MOP 74702). Funding of the PET camera system HRRT was supported by the Canada Foundation for Innovation, the Ontario Innovation Trust and the Ontario Research and Development Challenge Fund. Dr. Mizrahi is supported by the Canadian Institutes of Health Research (CIHR) New Investigator's Award and the Ontario Mental Health Foundation New Investigator Fellowship.

Contributors

Kapur, S. and Mizrahi, R. designed the study and wrote the protocol. Mizrahi, R. undertook the statistical analysis and wrote the draft of the manuscript.

Agid, O., Remington, G., and Borlido, C. were involved in clinical interview and subject recruitment. Suridjan,I. and Rusjan, P., Alan, W., and Houle, W. were involved in the imaging data analysis. All authors contributed to and have approved the final manuscript.

Conflict of interest

The corresponding author has nothing to disclose. Authors claim no conflict of interests.

Acknowledgments

Supported by the Canadian Institutes of Health Research (CIHR), Canada Foundation for Innovation (CFI) and the Ontario Ministry of Research and Innovation. Dr. Mizrahi is supported by the New Investigator Award from CIHR and the Ontario Mental Health Foundation (OMHF) New Investigator Fellowship.

The authors are grateful to Armando Garcia, Winston Stableford, Min Wong, Alvina Ng, Terry Bell, Ted Harris-Brandts and Peter Bloomfield.

References (49)

  • M. Willeit et al.

    High-affinity states of human brain dopamine D2/3 receptors imaged by the agonist [11C]-(+)-PHNO

    Biol. Psychiatry

    (2006)
  • W. Abi-Saab et al.

    First demonstration of D3 occupancy in humans: blockade of [11C]-(+)-PHNO PET by ABT-925

  • T.R. Barnes

    A rating scale for drug-induced akathisia

    Br. J. Psychiatry

    (1989)
  • I. Boileau et al.

    Decreased binding of the D3 dopamine receptor-preferring ligand [11C]-(+)-PHNO in drug-naive Parkinson's disease

    Brain

    (2009)
  • L. Farde et al.

    Central D2-dopamine receptor occupancy in schizophrenic patients treated with antipsychotic drugs

    Arch. Gen. Psychiatry

    (1988)
  • W.J. Florijn et al.

    Dopamine receptor subtypes: differential regulation after 8 months treatment with antipsychotic drugs

    J. Pharmacol. Exp. Ther.

    (1997)
  • S.B. Freedman et al.

    Expression and pharmacological characterization of the human D3 dopamine receptor

    J. Pharmacol. Exp. Ther.

    (1994)
  • J. Gallezot et al.

    [11C]-PHNO studies in rhesus monkey: in vivo affinity for D2 and D3 receptors and dosimetry

    (2009)
  • J.-D. Gallezot et al.

    [11C]PHNO studies in rhesus monkey: in vivo affinity for D2 and D3 receptors and dosimetry

    J. Nucl. Med.

    (2009)
  • N. Ginovart et al.

    Binding characteristics and sensitivity to endogenous dopamine of [11C]-(+)-PHNO, a new agonist radiotracer for imaging the high-affinity state of D2 receptors in vivo using positron emission tomography

    J. Neurochem.

    (2006)
  • N. Ginovart et al.

    Positron emission tomography quantification of [11C]-(+)-PHNO binding in the human brain

    J. Cereb. Blood Flow Metab.

    (2007)
  • R.R. Girgis et al.

    In vivo binding of antipsychotics to D(3) and D(2) receptors: a PET study in baboons with [(11)C]-(+)-PHNO

    Neuropsychopharmacology

    (2011)
  • A. Graff-Guerrero et al.

    The effect of antipsychotics on the high-affinity state of D2 and D3 receptors: a positron emission tomography study with [11C]-(+)-PHNO

    Arch. Gen. Psychiatry

    (2009)
  • R.N. Gunn et al.

    Positron emission tomography compartmental models: a basis pursuit strategy for kinetic modeling

    J. Cereb. Blood Flow Metab.

    (2002)
  • Cited by (74)

    • Association of dopamine D<inf>2/3</inf> receptor binding potential measured using PET and [<sup>11</sup>C]-(+)-PHNO with post-mortem DRD<inf>2/3</inf> gene expression in the human brain

      2020, NeuroImage
      Citation Excerpt :

      Labelled with carbon-11, (+)-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-ol ([11C]-(+)-PHNO) (Wilson et al., 2005), a radioligand with full agonistic properties at dopamine D2/3 receptors (Brown et al., 1997) offers an excellent signal-to-noise (SNR) ratio and favourable kinetics for PET imaging in humans (Ginovart et al., 2007; Jensen et al., 2007). Many studies using [11C]-(+)-PHNO have focused on schizophrenia (Graff-Guerrero et al., 2009; Mizrahi et al., 2012; Mizrahi et al., 2011; Mizrahi et al., 2014; Suridjan et al., 2013; Weidenauer et al., 2020), or substance use disorders (Boileau et al., 2015; Boileau et al., 2012; Payer et al., 2014; Worhunsky et al., 2017). Applying PET, several approaches have been described to determine the relative affinity of [11C]-(+)-PHNO as well as the regionally distinctive topology of D2 compared to D3 receptors, including pharmacological and animal studies (Graff-Guerrero et al., 2009).

    View all citing articles on Scopus
    View full text