Quantification of Ligand PET Studies using a Reference Region with a Displaceable Fraction: Application to Occupancy Studies with [¹¹C]-DASB as an Example

Abstract

This paper aims to build novel methodology for the use of a reference region with specific binding for the quantification of brain studies with radioligands and positron emission tomography (PET). In particular: (1) we introduce a definition of binding potential BP D = DVRÀ1 where DVR is the volume of distribution relative to a reference tissue that contains ligand in specifically bound form, (2) we validate a numerical methodology, rank-shaping regularization of exponential spectral analysis (RS-ESA), for the calculation of BP D that can cope with a reference region with specific bound ligand, (3) we demonstrate the use of RS-ESA for the accurate estimation of drug occupancies with the use of correction factors to account for the specific binding in the reference. [11 C]-DASB with cerebellum as a reference was chosen as an example to validate the methodology. Two data sets were used; four normal subjects scanned after infusion of citalopram or placebo and further six test-retest data sets. In the drug occupancy study, the use of RS-ESA with cerebellar input plus corrections produced estimates of occupancy very close the ones obtained with plasma input. Test-retest results demonstrated a tight linear relationship between BP D calculated either with plasma or with a reference input and high reproducibility.

Adenosine 2A Receptor Occupancy by Tozadenant and Preladenant in Rhesus Monkeys

“…It is therefore unclear whether this reduction is due to blocking of specific binding in the cerebellum (unlikely because of the dose independence) or other factors such as small changes in the plasma protein binding that would be difficult to detect given the low free fraction (;1%). However, if one conservatively assumes a specific signal in the cerebellum of 20% of the total signal, occupancy measurement error (maximum, ;50% occupancy) would be less than 5% (27,28). The excellent agreement in the occupancy estimates between the plasma-based and reference region-based methods suggests that A 2A occupancy can be quantitatively assessed in rhesus monkeys using SRTM or NI-LGA without the need for arterial sampling.…”

Measuring specific receptor binding of a PET radioligand in human brain without pharmacological blockade: The genomic plot

“…It should be noted that, compared to other studies in which only a single tracer was used for validation (e.g. Cunningham et al, 2010 or Turkheimer et al, 2012), the applicability of the methodology presented in this study was tested on multiple tracers directed to different brain systems. In particular, the use of nonhuman primate data can be justified under several aspects: 1) Nonhuman primate data have been used to validate the Lassen plot (e.g.…”

“…The radioligand concentration in this region then becomes the reference for all regions, because the nondisplaceable binding is generally assumed to be constant in the brain (Lammertsma and Hume, 1996). Many receptors are however expressed across the whole human brain, and therefore a reference region is rarely available (Turkheimer et al, 2012). In these instances, measuring the nondisplaceable fraction requires an additional scan after administration of a competitive blocking agent (Lassen et al, 1995).…”

In Vivo Assessment and Dosimetry of 2 Novel PDE10A PET Radiotracers in Humans: 18F-MNI-659 and 18F-MNI-654

“…Further work is needed to fully validate the use of the cerebellum as a reference region for quantification of the PDE10A signal with 18 F-MNI-659 in the human brain or at least estimate the bias or level of specific binding in that region, compared with the nonspecific and free signal (37)(38)(39). Moreover, it would be useful to further assess the bias due to SRTM assumption violation and sensitivity due to changes in the cerebral blood flow using a simulated dataset (37,40).…”