In vivo and in vitro validation of reference tissue models for the mGluR(5) ligand [(11)C]ABP688.
The primary objective of this study was to verify the suitability of reference tissue-based quantification methods of the metabotropic glutamate receptor type 5 (mGluR(5)) with [(11)C]ABP688. This study presents in vivo (Positron Emission Tomography (PET)) and in vitro (autoradiography) measurements of mGluR(5) densities in the same rats and evaluates both noninvasive and blood-dependent pharmacokinetic models for the quantification of [(11)C]ABP688 binding. Eleven rats underwent [(11)C]ABP688 PET scans. In five animals, baseline scans were compared with blockade experiments with the antagonist 1,2-methyl-6-(phenylethynyl)-pyridine (MPEP), and arterial blood samples were drawn and corrected for metabolites. Afterward, saturation-binding autoradiography was performed. Blocking with MPEP resulted in an average decrease of the total distribution volume (V(T)) between 43% and 58% (thalamus and caudate-putamen, respectively) but had no significant effect on cerebellar V(T) (mean reduction: -0.01%). Comparing binding potential (BP(ND)) based on the V(T) with noninvasively determined BP(ND) revealed an average negative bias of 0.7% in the caudate-putamen and an average positive bias of 3.1% in the low-binding regions. Scan duration of 50 minutes is required. The cerebellum is a suitable reference region for the quantification of mGluR(5) availability as measured with [(11)C]ABP688 PET in rats. Blood-based and reference region-based PET quantification shows a significant linear relationship to autoradiographic determinations.
Institute of Neurosciences and Medicine, INM-2, Research Center Juelich, Juelich, Germany.
David
D
Elmenhorst
Luciano
L
Minuzzi
Antonio
A
Aliaga
Jared
J
Rowley
Gassan
G
Massarweh
Mirko
M
Diksic
Andreas
A
Bauer
Pedro
P
Rosa-Neto
D000818:Animals; D001345:Autoradiography / Q000379:methods; D001665:Binding Sites; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism; D002250:Carbon Radioisotopes / Q000032:analysis / Q000378:metabolism / Q000493:pharmacokinetics; D007700:Kinetics; D008297:Male; D010091:Oximes / Q000032:analysis / Q000378:metabolism* / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography / Q000379:methods*; D011725:Pyridines / Q000032:analysis / Q000378:metabolism* / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000032:analysis / Q000378:metabolism*
C510950:3-(6-methylpyridin-2-ylethynyl)cyclohex-2-enone-O-methyloxime; D002250:Carbon Radioisotopes; D010091:Oximes; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate