In vitro binding of [11C]raclopride with ultrahigh specific activity in rat brain determined by homogenate assay and autoradiography

doi:10.1016/j.nucmedbio.2007.09.009

Nuclear Medicine and Biology

Volume 35, Issue 1, January 2008, Pages 19-27

https://doi.org/10.1016/j.nucmedbio.2007.09.009 Get rights and content

Abstract

Objective

The aim of this study was to characterize the in vitro binding of [¹¹C]raclopride with ultrahigh specific activity (SA) in the striatum and cerebral cortex of rat brain.

Methods

[¹¹C]Raclopride, a dopamine D₂ receptor ligand, with an ultrahigh SA of 4880±2360 GBq/μmol (132±64 Ci/μmol, n=25) was synthesized. In vitro binding experiment was performed using brain homogenate assay and autoradiography (ARG).

Results

In vitro homogenate assay demonstrated that high SA [¹¹C]raclopride (2520–6340 GBq/μmol; 68–171 Ci/μmol) had two-affinity (high and low) binding sites in the striatum and cerebral cortex of rat brain. In the striatum, K_d,high and B_max,high values were 0.005±0.002 nM and 0.19±0.04 fmol/mg tissue, respectively, while K_d,low and B_max,low values were 2.2±1.0 nM and 35.8±16.4 fmol/mg tissue, respectively. In the cerebral cortex, K_d,high and B_max,high values were 0.061±0.087 nM and 0.2±0.2 fmol/mg tissue, respectively, while K_d,low and B_max,low values were 2.5±3.2 nM and 5.5±4.8 fmol/mg tissue, respectively. On the other hand, only one binding site was found in the striatum and no binding site was identified in the cerebral cortex using low SA [¹¹C]raclopride (44 GBq/μmol; 1.2 Ci/μmol). In vitro ARG for the rat brain using high SA [¹¹C]raclopride (6212 GBq/μmol; 168 Ci/μmol) gave a coronal image of the striatum and cerebral cortex with a higher signal/noise ratio than using low SA [¹¹C]raclopride (40 GBq/μmol; 1.1 Ci/μmol).

Conclusion

Using ultrahigh SA [¹¹C]raclopride for the in vitro homogenate assay, we succeeded in detecting two-affinity binding sites of [¹¹C]raclopride, not only in the striatum but also in the cerebral cortex of rat brain.

Introduction

Various kinds of radioisotopes and their labeled compounds have been developed for investigating brain receptors with positron emission tomography (PET) and autoradiography (ARG). PET combined with various radioligands makes it possible to assess specific receptor systems noninvasively in the brain. Using PET, the central dopaminergic systems have been studied in relation to the pathophysiology of several neuropsychiatric disorders [1], [2], [3], [4], [5], [6]. Pharmacological studies on dopamine D₂ receptor in schizophrenia have indicated that the extrastriatal D₂ receptor is a common action site of some antipsychotics [7], [8], [9]. Therefore, PET study on the D₂ receptor has focused not only on the striatum, which is the main region with high dopamine receptor density, but also on extrastriatal D₂ regions especially in the cerebral cortex [10], [11], [12], [13], [14].

[¹¹C]Raclopride, [¹¹C]FLB457 and [¹⁸F]fallypride, which are selective and potent PET ligands for the D₂ receptor, have been used to search for the receptor in the cerebral cortex of the human brain in vivo [11], [12], [13], [14], [15], [16], [17], [18], [19]. However, since the carrier mixed with the radioligand binds to this receptor competitively, measuring specific D₂ binding in low-density regions of rodents and primates is easily disturbed by a high level of nonspecific binding. In fact, quantitative data about the D₂ density in these regions were sometimes indefinite and controversial [20], [21], [22], [23], [24], [25]. Therefore, characterizing the D₂ receptor in these regions such as the cerebral cortex using a PET ligand remains a challenging research task.

An effective method to measure D₂ density in the cerebral cortex is to decrease the amount of carrier mixing with the radioligand. The radioligand used for the binding study should have extremely high specific activity (SA) to decrease nonspecific binding due to the carrier. However, it was difficult to achieve a high SA of >740 GBq/μmol (20 Ci/μmol) ligand due to isotopic dilution by various contamination sources [26], [27]. Recently, we have developed an automatic synthesis system for preparing [¹¹C]ligand with ultrahigh SA [28], [29]. To achieve and keep this level of SA, we have made the following efforts: (a) machining of the chamber body of irradiation target without oil and successive washing, vacuum drying, cooling down and assembling the target chamber under inert atmosphere; (b) adoption of the single-pass I₂ method and in situ production of [¹¹C]CH₄ in the target chamber; (c) several times preirradiation for a short period just before real production [28]. Owing to these treatments, we succeeded in producing several PET ligands such as [¹¹C]Ro15-4513 and [¹¹C]PE2I with an SA of 4700±2500 GBq/μmol (127±68 Ci/μmol) for in vitro and in vivo evaluation in rodent brains [28], [29].

In this study, to widen the usefulness of high SA, we firstly synthesized [¹¹C]raclopride, a standard PET ligand for the D₂ receptor, with an ultrahigh SA of 4880±2360 GBq/μmol (132±64 Ci/μmol, n=25). Then, using this ligand, we performed homogenate assay and ARG to characterize its in vitro binding in the cerebral cortex and striatum of rat brains.

For convenience, “specific activity,” “ultrahigh specific activity” (2520–7240 GBq/μmol; 68–196 Ci/μmol) and “conventional specific activity” (33–104 GBq/μmol; 1.0–2.8 Ci/μmol) were simplified as “SA,” “high SA” and “low SA,” respectively, in this article.

Section snippets

Radiolabeling

Carbon-11 with total radioactivity of about 44 GBq (1.2 Ci) was produced by ¹⁴N(p, α)¹¹C nuclear reaction using CYPRIS HM-18 cyclotron (Sumitomo Heavy Industry Co. Ltd., Tokyo, Japan). [¹¹C]CH₃I was prepared by the single-pass I₂ method as described previously [28] and then converted to [¹¹C]CH₃OTf [30], which was collected in the reaction vessel containing a 500-μl acetone solution of desmethyl precursor (0.5 mg, ABX, Radeberg, Germany) and NaH (0.5 N, 4 μl) at room temperature. After the

Results

With the SA of 4880±2360 GBq/μmol (132±64 Ci/μmol, EOS, n=25), [¹¹C]raclopride was synthesized at a yield of 780±320 MBq (21±9 mCi) with a radiochemical purity of >98% within 31 min from the end of bombardment. The carrier amount in the final product solution (1 ml) was measured using a highly sensitive fluorescence detector [32]. The limit of this detector was 0.075 pmol/ml.

Fig. 1 shows [¹¹C]raclopride binding in the striatum of rat brain under various ligand concentrations. Saturation curves

Discussion

In this study, the in vitro homogenate assay demonstrated that high SA [¹¹C]raclopride had two-affinity binding sites in the striatum and cerebral cortex of the rat brain, which has not been reported previously. Many in vitro binding experiments using [³H]raclopride were performed to characterize ligand binding to the D₂ receptor in the rat brain. Kohler et al. [33] reported that the K_d and B_max values of [³H]raclopride were 1.2±0.1 nM and 23.5±2.2 pmol/g wet tissue in the rat brain,

Conclusions

Using high SA [¹¹C]raclopride for the in vitro homogenate assay, we succeeded in detecting two-affinity binding sites of [¹¹C]raclopride, not only in the striatum but also in the cerebral cortex of rat brain. Moreover, high SA [¹¹C]raclopride provided a clearer autoradiographic image exhibiting higher radioactivity in the striatum and cerebral cortex than low SA [¹¹C]raclopride under the same radioactivity. In vivo investigation of rodents and primates using high SA [¹¹C]raclopride is under way.

Acknowledgments

We thank Dr. Y. Fanaki (Cyclotron and Radioisotope Center, Tohoku University) for instruction on the in vitro homogenate assay. We also thank Mr. M. Takei (Tokyo Nuclear Service) and Mrs. N. Nengaki, M. Ogawa and K. Furutsuka (SHI Accelerator Service) for their technical support on the radiosynthesis and analysis procedures. This study was supported in part by a Grant-in-Aid for the Molecular Imaging Program from the Ministry of Education, Culture, Sports, Science and Technology of the Japanese

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In vitro binding of [11C]raclopride with ultrahigh specific activity in rat brain determined by homogenate assay and autoradiography

Abstract

Objective

Methods

Results

Conclusion

Introduction

Section snippets

Radiolabeling

Results

Discussion

Conclusions

Acknowledgments

Quantitative analysis of D2 dopamine receptor binding in the living human brain by PET

Science

PET studies of dopamine receptors in relation to antipsychotic drug treatment

Clin Neuropharmacol

Central D2-dopamine receptor occupancy in relation to antipsychotic drug effects: a double-blind PET study of schizophrenic patients

Biol Psychiatry

PET study on striatal dopamine D2 receptor changes during the progression of early Parkinson's disease

Mov Disord

Effects of repetitive transcranial magnetic stimulation on [(11)C]raclopride binding and cognitive function in patients with depression

J Affect Disord

Is psychological stress in man associated with increased striatal dopamine levels? A [(11)C]raclopride PET study

Synapse

Differential regulation of D2 and D4 dopamine receptor mRNAs in the primate cerebral cortex vs. neostriatum: effects of chronic treatment with typical and atypical antipsychotic drugs

J Pharmacol Exper Ther

Parametric mapping of binding in human brain of D2 receptor ligands of different affinities

J Nucl Med

The striatal and extrastriatal D2/D3 receptor-binding profile of clozapine in patients with schizophrenia

Neuropsychopharmacology

Stereoselective binding of 11C-raclopride in living human brain a search for extrastriatal central D2-dopamine receptor by PET

Psychopharmacology

Quantitation of extrastriatal D2 receptors using a very high-affinity ligand (FLB 457) and the multi-injection approach

J Cereb Blood Flow Metab

Extrastriatal dopamine D2 receptor density and affinity in the human brain measured by 3D PET

Int J Neuropsychopharmacol

Amphetamine-induced displacement of [18F]fallypride in striatum and extrastriatal regions in humans

Neuropsychopharmacology

Conditioned dopamine release in humans: a positron emission tomography [11C]raclopride study with amphetamine

J Neurosci

A PET-study of [11C]FLB 457 binding to extrastriatal D2-dopamine receptors in healthy subjects and antipsychotic drug-treated patients

Psychopharmacology

Quantification of [11C]FLB 457 binding to extrastriatal dopamine receptors in the human brain

J Cereb Blood Flow Metab

Reproducibility of [11C]FLB 457 binding in extrastriatal regions

Nucl Med Commun

Effect of amphetamine on [(18)F]fallypride in vivo binding to D(2) receptors in striatal and extrastriatal regions of the primate brain: single bolus and bolus plus constant infusion studies

Synapse

In vitro binding of [¹¹C]raclopride with ultrahigh specific activity in rat brain determined by homogenate assay and autoradiography

Differential regulation of D₂ and D₄ dopamine receptor mRNAs in the primate cerebral cortex vs. neostriatum: effects of chronic treatment with typical and atypical antipsychotic drugs

Stereoselective binding of ¹¹C-raclopride in living human brain a search for extrastriatal central D₂-dopamine receptor by PET

Amphetamine-induced displacement of [¹⁸F]fallypride in striatum and extrastriatal regions in humans

A PET-study of [¹¹C]FLB 457 binding to extrastriatal D2-dopamine receptors in healthy subjects and antipsychotic drug-treated patients

Quantification of [¹¹C]FLB 457 binding to extrastriatal dopamine receptors in the human brain

Reproducibility of [¹¹C]FLB 457 binding in extrastriatal regions