Development of a simultaneous PET/microdialysis method to identify the optimal dose of 11C-raclopride for small animal imaging

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Abstract

In the field of small animal positron emission tomography (PET), the assumptions underlying human and primate kinetic models may not be sustained in rodents. That is, the threshold dose at which a pharmacologic response occurs may be lower in small animals. In order to define this relationship, we combined microPET imaging using 11C-raclopride with microdialysis measures of extracellular fluid (ECF) dopamine (DA). In addition, we performed a series of studies in which a known mass of raclopride was microinfused into one striatum prior to a high specific activity (SA) systemic injection of 11C-raclopride. This single-injection approach provided a high and low SA region of radiotracer binding in the same animal during the same scanning session. Our data demonstrate that the binding potential (BP) declines above 3.5 pmol/ml (0.35 μg), with an ED50 of 8.55 ± 5.62 pmol/ml. These data also provide evidence that BP may be compromised by masses of raclopride below 2.0 pmol/ml (0.326 μg). Increases in ECF DA were produced by mass doses of raclopride over 3.9 pmol/ml (0.329 μg) with an ED50 of 8.53 ± 2.48 pmol/ml. Taken together, it appears that an optimal range of raclopride mass exists between 2.0 and 3.5 pmol/ml, around which the measured BP can be compromised by system sensitivity, endogenous DA, or excessive competition with unlabeled compound.

Section snippets

Materials and methods

This work was approved by the BNL IACUC. Forty eight (48) adult male Sprague–Dawley (Taconic Farms, New York) rodents weighing 275–300 g were used for this experiment. All animals were housed and maintained in an AAALAC accredited veterinary facility.

Results

Microdialysis was combined with microPET imaging to establish a range of raclopride mass that decreased 11C-raclopride BP and increased ECF DA. For the microdialysis measures of extracellular DA, our calculated extraction fraction of 0.3 was applied to the measured concentration of DA in the dialysate to correct for the efficiency of the transfer between tissue and probe. Using this correction, our basal levels of extracellular DA varied considerably across animals, with average values of 86.94 ±

Discussion

In the present study, we developed a novel experimental methodology in order to obtain multiple discrete measures of neurotransmitter activity and receptor density using in vivo microdialysis sampling and microPET imaging, respectively, in the same animal. We then applied this approach to independently examine the tolerance of striatal DA systems to increasing mass doses of 11C-raclopride. By combining these two measures, we independently determined the range of influence each measure exerts on

Acknowledgements

We greatly appreciate the tremendous efforts of the BNL Cyclotron (Mike Schueller, Paul Vaska, David Schlyer, Victor Garza, and Frank Zafonte) and assistance provided by Jim Anselmini and Lee Wolcott in the Chemistry Department. We are also grateful for funding support provided by NIH/NIDA in the form of a predoctoral fellowship to W.K.S. (F31-DA15874) and RO1 to S.L.D. (DA015041), and also the U.S. Department of Energy Office of Biological and Environmental Research (USDOE/OBER

References (36)

  • H. Benveniste

    Brain microdialysis

    J Neurochem

    (1989)
  • J. Delforge et al.

    Absolute quantification by positron emission tomography of the endogenous ligand

    J Cereb Blood Flow Metab

    (2001)
  • S.L. Dewey et al.

    Positron emission tomography (PET) studies of dopaminergic/cholinergic interactions in the baboon brain

    Synapse

    (1990)
  • S.L. Dewey et al.

    Striatal binding of the PET ligand 11C-raclopride is altered by drugs that modify synaptic dopamine levels

    Synapse

    (1993)
  • S.L. Dewey et al.

    The effects of central cholinergic blockage on [18F]-N-methylspiroperidol binding in the human brain using PET

    XVI CINP Congr

    (1988)
  • D.J. Doudet et al.

    In vivo measurement of receptor density and affinity: comparison of the routine sequential method with a nonsequential method in studies of dopamine D2 receptors with [11C]raclopride

    J Cereb Blood Flow Metab

    (2003)
  • L. Farde et al.

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

    Science

    (1986)
  • A. Gjedde et al.

    Quantification of neuroreceptors in living human brain. V. Endogenous neurotransmitter inhibition of haloperidol binding in psychosis

    J Cereb Blood Flow Metab

    (2001)
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