[123I]Epidepride binding to cerebellar dopamine D2/D3 receptors is displaceable: Implications for the use of cerebellum as a reference region

doi:10.1016/j.neuroimage.2006.11.003

NeuroImage

Volume 34, Issue 4, 15 February 2007, Pages 1450-1453

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Abstract

The low density of cerebellar dopamine D₂/D₃ receptors provides the basis for using the cerebellum as a representation of free- and non-specifically bound radioligand in positron emission tomography (PET) and single photon emission computed tomography (SPECT) studies. With the development of ultra high-affinity dopamine D₂/D₃ ligands like [¹²³I]epidepride, [¹⁸F]fallypride, and [¹¹C]FLB-457, quantification of extrastriatal low density receptor populations including the cerebellum is possible with important implications for calculation of binding parameters. [¹²³I]epidepride-SPECT was performed in 23 patients with schizophrenia before and after 3 months of antipsychotic treatment with either risperidone (n = 14) or zuclopenthixol (n = 9). In the unblocked situation and partially blocked situation, the average distribution volumes were 5.2 ± 1.3 mL/mL and 4.0 ± 0.8 mL/mL, respectively. The paired distribution volumes were reduced by 22 ± 15% (mean ± SD) after antipsychotic treatment (p < 0.0001, paired Student’s t-test). From the paired distribution volumes in cerebellum and extrastriatal regions, the average distribution volume representing free and non-specifically bound [¹²³I]epidepride was calculated to be 3.3 ± 0.8 mL/mL. Both the % [¹²³I]epidepride fraction of plasma radioactivity (p > 0.76) and the plasma [¹²³I]epidepride concentration (p > 0.45) were unchanged after antipsychotic treatment (paired Student’s t-test). These results strongly suggest the presence of “non-negligible” specific [¹²³I]epidepride binding to dopamine D₂/D₃ receptors in the cerebellum. Using the cerebellum as a representation of free and non-specifically bound radioligand and neglecting the specifically bound component may lead to results that erroneously imply that antipsychotic drugs bind to extrastriatal dopamine D₂/D₃ receptors with a higher affinity than to striatal dopamine D₂/D₃ receptors.

Introduction

The interest in quantification of extrastriatal dopamine D₂/D₃ receptor density using positron emission tomography (PET) or single photon emission computed tomography (SPECT) begins with the hypothesis that extrastriatal dopamine D₂ receptors are involved in the pathophysiology of schizophrenia and in the mechanism of antipsychotic drug action. [¹²³I]epidepride, [¹⁸F]fallypride, and [¹¹C]FLB-457 are members of a family of ultra high-affinity dopamine receptor antagonist radioligands that were originally derived from the structure of (S)-sulpride and remoxipride (de Paulis, 2003). Their affinities (1 / K_d) for the primate dopamine D₂/D₃ receptors are in the picomolar range, which allow for quantification and visualization of low density extrastriatal receptors D₂/D₃ receptors. In comparison, the widely used radioligands [¹¹C]raclopride and [¹²³I]IBZM show 10- to 50-fold lower affinities for primate D₂/D₃ receptors, thereby precluding quantification of extrastriatal D₂/D₃ receptors due to a poor target-to-background ratio.

Most in vivo quantification of dopamine D₂/D₃ receptor density with these radioligands uses uptake in cerebellum as a representation of free and non-specifically bound radioligand. This practice is based upon the assumption that only a “negligible” density of dopamine D₂/D₃ receptors is present in the cerebellum (Varrone et al., 2000). Several studies using ultra high-affinity dopamine D₂/D₃ radioligands have challenged the validity of this assumption. Ito et al. (2001) reported that following bolus injection of [¹¹C]FLB-457 at high specific activity a two-tissue compartment model fitted cerebellar data significantly better than a one-tissue compartment model. Olsson et al. (2004) reported that the area under the normalized cerebellar [¹¹C]FLB-457 time–activity curve was significantly reduced by 11.1 ± 8.1% (mean ± SD) after injection of tracer at low specific activity compared to injection of tracer at high specific activity. In this study, we present [¹²³I]epidepride-SPECT cerebellar data from 23 schizophrenic patients studied twice: before and after 3 months of antipsychotic treatment. Cerebellar distribution volumes were calculated as simple tissue to plasma ratios following bolus/infusion administration of tracer aiming at producing tracer steady state in cerebellum and plasma.

Section snippets

Materials and methods

The studies were performed in twenty-three patients (19–37 years of age), all meeting the ICD-10 criteria for schizophrenia. All patients gave informed written consent. The ethical committee of Copenhagen and Frederiksberg has approved the study (KF 01-078/97 + 01-012/98). Patients were admitted to treatment for the first time, and none of the patients had ever received any antipsychotic drugs. The patients were randomly allocated to two treatment groups; one group (n = 9) was treated with 9.6 ±

Results

Fig. 1 shows the paired distribution volumes in the unblocked and partially blocked situation. In the unblocked situation and partially blocked situation, the average distribution volumes were 5.2 ± 1.3 mL/mL and 4.0 ± 0.8 mL/mL, respectively. The distribution volume was reduced by 22 ± 15% (mean ± SD) after antipsychotic treatment (p < 0.0001, paired Student’s t-test). There was no significant difference between the reductions in distribution volumes after antipsychotic treatment in the risperidone

Discussion

For quantification of regional neuroreceptor binding potential using SPECT and PET, calculation of the binding potential depends upon using a reference tissue as a representation of free and non-specifically bound radioligand. Autoradiographic studies have demonstrated a very low density of cerebellar dopamine D₂/D₃ receptors (Martres et al., 1985, Kessler et al., 1993, Hall et al., 1996). Thus, using radioligands like [¹¹C]raclopride and [¹²³I]IBZM with a moderate to high dopamine D₂/D₃

Acknowledgments

We thank Bente Dall and Eva Brodsgaard for expert technical assistance. The study was sponsored by The Danish Medical Research Council, H:S (Copenhagen Hospital Cooperation) Research Council, Copenhagen University Hospital, H:S Bispebjerg, an unrestricted grant from Janssen-Cilag A/S, and the Novo Nordic Foundation.

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[123I]Epidepride binding to cerebellar dopamine D2/D3 receptors is displaceable: Implications for the use of cerebellum as a reference region

Abstract

Introduction

Section snippets

Materials and methods

Results

Discussion

Acknowledgments

NeuroImage

Brain Res.

Biol. Psychiatry

NeuroImage

In vitro and in vivo characterisation of nor-beta-CIT: a potential radioligand for visualization of the serotonin transporter in the brain

Eur. J. Nucl. Med.

A method for attenuation correction in computed tomography

IEEE Trans. Nucl. Sci.

[¹²³I]Epidepride binding to cerebellar dopamine D₂/D₃ receptors is displaceable: Implications for the use of cerebellum as a reference region