Evaluation of Reference Tissue Models for the Analysis of [¹¹C](R)-PK11195 Studies

Abstract

[ 11 C](R)-PK11195 is a marker of activated microglia, which can be used to measure inflammation in neurologic disorders. The purpose of the present study was to define the optimal reference tissue model based on a comparison with a validated plasma input model and using clinical studies and Monte Carlo simulations. Accuracy and reproducibility of reference tissue models were evaluated using Monte Carlo simulations. The effects of noise and variation in specific binding, nonspecific binding and blood volume were evaluated. Dynamic positron emission tomography scans were performed on 13 subjects, and radioactivity in arterial blood was monitored online. In addition, blood samples were taken to generate a metabolite corrected plasma input function. Both a (validated) two-tissue reversible compartment model with K 1 /k 2 fixed to whole cortex and various reference tissue models were fitted to the data. Finally, a simplified reference tissue model (SRTM) corrected for nonspecific binding using plasma input data (SRTM pl_corr ) was investigated. Correlations between reference tissue models (including SRTM pl_corr ) and the plasma input model were calculated. Monte Carlo simulations indicated that low-specific binding results in decreased accuracy and reproducibility. In this respect, the SRTM and SRTM pl_corr performed relatively well. Varying blood volume had no effect on performance. In the clinical evaluation, SRTM pl_corr and SRTM had the highest correlations with the plasma input model (R 2 = 0.82 and 0.78, respectively). SRTM pl_corr is optimal when an arterial plasma input curve is available. Simplified reference tissue model is the best alternative when no plasma input is available. Keywords: microglia; peripheral benzodiazepine receptor; PET (positron emission tomography); PK11195; reference tissue models; tracer kinetic modelling IntroductionCarbon-11 labeled (R)-PK11195 ((R)-1-(2-chlorophenyl)-N-[ 11 C]methyl-N-(1-methylpropyl)-3-isoquinoline carboxamide) is a ligand for the peripheral benzodiazepine receptor. In the brain, this receptor is mainly expressed on activated microglia (Banati et al, 1997). Both [ 11 C](R)-PK11195 and [ 11 C]PK11195 have been used as positron emmision tomography (PET) tracers to study activated microglia in various neurologic disorders. It has been used to study stroke (Ramsay et al, 1992;Pappata et al, 2000;Gerhard et al, 2000Gerhard et al, , 2005a), Alzheimer's disease (Groom et al, 1995; Cagnin et al, 2001a;Versijpt et al, 2003), multiple sclerosis (Banati et al, 2000;Debruyne et al, 2002Debruyne et al, , 2003Versijpt et al, 2005) and various other diseases (Pappata et al, 1991; Banati et al, 1999Banati et al, , 2001Goerres et al, 2001;Cagnin et al, 2001bCagnin et al, , 2004Cicchetti et al, 2002;Gerhard et al, 2003Gerhard et al, , 2004Gerhard et al, , 2005bTurner et al, 2004Turner et al, , 2005Venneti et al, 2004;Henkel et al, 2004;Ouchi et al, 2005). Most studies have used a reference tissue approach to quantify binding, either by applying the simplified reference tissue mod...

11C-ER176, a Radioligand for 18-kDa Translocator Protein, Has Adequate Sensitivity to Robustly Image All Three Affinity Genotypes in Human Brain

“…A similar interaction may occur for TSPO with any of the 3 proteins that combine with TSPO to form the so-called permeability transition pore (25,26). In addition, the higher specific binding of improved radioligands may increase in vivo sensitivity to the genotype, in contrast to the prototypical agent 11 C-(R)-PK11195 that has a relatively lower signal-to-noise ratio in brain and may lack the sensitivity needed to detect a genetic effect (4,5,7).…”

“…However, these radioligands have a relatively low signal-to-noise ratio. For example, the ratio of specific to nonspecific binding of 11 C-(R)-PK11195 in human brain was reported to be only about 0.2-0.5 (4,5). In contrast, some second-generation radioligands for TSPO, such as [methyl-11 C]N-acetyl-N-(2-methoxybenzyl)-2-phenoxy-5-pyridinamine) ( 11 C-PBR28), have a higher in vivo specific signal to TSPO than 11 C-(R)-PK11195.…”

Kinetic models for analysing myocardial [11C]palmitate data

“…As both physiological description and clinical consequences of [ 11 C]palmitate model choice have previously been discussed in detail [9,11,23,24], the present study focused on the applicability of these models within spatial and temporal limitations of the PET data. To assess how many parameters could be determined from human [ 11 C]palmitate studies, models of different levels of complexity were compared systematically, in each case relating the model to the underlying physiology [25][26][27].…”

Kinetic analysis in healthy humans of a novel positron emission tomography radioligand to image the peripheral benzodiazepine receptor, a potential biomarker for inflammation

“…Such washing is not possible for in vivo imaging, and [ 11 C]PK 11195 has relatively low ratios of specific to nonspecific binding. For example, by using reference tissue models, Kropholler et al have reported that the ratio of specific to nonspecific binding of the active enantiomer (R) of [ 11 C]PK 11195 in human brain is only about 0.2 -0.5 (Kropholler et al, 2006).…”