Evaluation of [ 123I]IBZM pinhole SPECT for the detection of striatal dopamine D 2 receptor availability in rats

Abstract

Single photon emission computed tomography (SPECT) and MRI coregistration have been assessed to characterize striatal dopamine D 2/D 3 receptor (D 2/D 3R) availability in rats following injection of the D 2 and D 3R 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 D 2/D 3 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 D 2/D 3R 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 ( r 2 = 0.83; P < 0.001) whereas correlation with locomotor activity was less tight ( r 2 = 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 D 2/D 3R 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.