title: Evaluation of [123I]IBZM pinhole SPECT for the detection of striatal dopamine D2 receptor availability in rats.
abstract: Single photon emission computed tomography (SPECT) and MRI coregistration have been assessed to characterize striatal dopamine D2/D3 receptor (D2/D3R) availability in rats following injection of the D2 and D3R radioligand [123I] iodobenzamide ([123I]IBZM). High-resolution SPECT data were obtained with a pinhole collimator. In order to precisely estimate brain regions of low radioligand uptake, SPECT images were coregistered onto a MRI template with high accuracy (maximum mismatch 1.1 mm). To evaluate an adequate dose of radioligand to be administered without exceeding the radioligand-to-receptor occupancy >5% and to define an appropriate time period for image acquisition, three untreated groups of animals received 29.6, 37, and 44.4 MBq of [123I]IBZM and underwent five consecutive SPECT acquisitions lasting 64 min each. Ratio calculations between specific striatal radioligand uptake and nondisplaceable cerebellar uptake revealed a secular equilibrium between 75 and 355 min post-tracer application in all three animal groups. Consequently, since the highest regional uptake values were obtained in the animal group receiving 44.4 MBq [123I]IBZM, this injection dose was considered to be appropriate. Finally, the capacity of the imaging method to detect distinct severity levels of striatal dopamine D2/D3 receptor loss was tested in a low, medium, and high dose quinolinic acid (QA) animal model of Huntington's disease. Motor impairment indicative of striatal dysfunction was monitored using amphetamine-induced rotational behavior and locomotor activity. Loss of striatal D2/D3R bearing medium-sized spiny neurons was assessed by DARPP-32 immunohistochemistry and compared to [123I]IBZM binding. Optical density measures of DARPP-32 immunohistochemistry demonstrated QA dose-dependent mild to subtotal unilateral striatal lesions ranging from 29.4% to 96.9% when compared to the nonlesioned side. Linear regression analysis showed that measurements of striatal DARPP-32 optical density and striatal [123I]IBZM uptake of the lesioned side were highly correlated (r2=0.83; P<0.001) whereas correlation with locomotor activity was less tight (r2=0.23; P<0.05; amphetamine-induced rotational behavior was not significantly correlated). This is the first study to demonstrate that in vivo [123I]IBZM SPECT and MRI coregistration are highly sensitive and, in contrast to behavioral measures, accurately detect mild to subtotal striatal lesions by measuring loss of D2/D3R availability. SPECT-MRI-based estimation of regional [123I]IBZM uptake provides a cost effective and widely available in vivo imaging technique for assessing striatal integrity in animal studies.
authors.affiliation: Clinical Department of Neurology, Innsbruck Medical University, 6020 Innsbruck, Austria. christoph.scherfler@uibk.ac.at
authors.forename: Christoph
authors.initials: C
authors.lastname: Scherfler
authors.forename: Sonja W
authors.initials: SW
authors.lastname: Scholz
authors.forename: Eveline
authors.initials: E
authors.lastname: Donnemiller
authors.forename: Clemens
authors.initials: C
authors.lastname: Decristoforo
authors.forename: Michael
authors.initials: M
authors.lastname: Oberladstätter
authors.forename: Nadia
authors.initials: N
authors.lastname: Stefanova
authors.forename: Eric
authors.initials: E
authors.lastname: Diederen
authors.forename: Irene
authors.initials: I
authors.lastname: Virgolini
authors.forename: Werner
authors.initials: W
authors.lastname: Poewe
authors.forename: Gregor K
authors.initials: GK
authors.lastname: Wenning
mesh_terms: D000818:Animals; D001549:Benzamides / Q000493:pharmacokinetics; D001923:Brain Chemistry / Q000187:drug effects / Q000502:physiology; D018492:Dopamine Antagonists / Q000493:pharmacokinetics; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D015902:Gamma Cameras; D006816:Huntington Disease / Q000139:chemically induced / Q000473:pathology; D007090:Image Interpretation, Computer-Assisted; D007150:Immunohistochemistry; D016014:Linear Models; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D017072:Neostriatum / Q000000981:diagnostic imaging*; D009419:Nerve Tissue Proteins; D009474:Neurons / Q000502:physiology; D010750:Phosphoproteins; D011759:Pyrrolidines / Q000493:pharmacokinetics; D017378:Quinolinic Acid / Q000494:pharmacology; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods*
chemical_list: D001549:Benzamides; D018492:Dopamine Antagonists; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; D011759:Pyrrolidines; D019275:Radiopharmaceuticals; D017448:Receptors, Dopamine D2; D016194:Receptors, N-Methyl-D-Aspartate; C055743:3-iodo-2-hydroxy-6-methoxy-N-((1-ethyl-2-pyrrolidinyl)methyl)benzamide; D017378:Quinolinic Acid