Parametric Mapping of 5HT_1A Receptor Sites in the Human Brain with the Hypotime Method: Theory and Normal Values

Abstract

The radioligand [carbonyl-11 C]WAY-100635 ( 11 C-WAY) is a PET tracer of the serotonin 5HT 1A receptors in the human brain. It is metabolized so rapidly in the circulation that it behaves more as a chemical microsphere than as a tracer subject to continuous exchange between the circulation and brain tissue. Although reference tissue methods are useful as analyses of uptake of some radioligands with indeterminate arterial input functions, their use to analyze 11 C-WAY uptake and binding is challenged by the rapid plasma metabolism, which violates the assumption that regions of interest and reference regions continue to exchange radioligand with the circulation during the entire uptake period. Here, we proposed a method of calculation (Hypotime) that specifically uses the washout rather than the accumulation of 11 C-WAY to determine binding potentials (BP ND ), without the use of regression analysis. Methods: A total of 19 healthy volunteers (age range, 23-73 y) underwent PET to test the Hypotime application of the chemical microsphere properties of 11 C-WAY to identify regions of binding and nonbinding on the exclusive basis of the rate of washout of 11 C-WAY. Results: The results of the Hypotime method were compared with the simplified but multilinearized reference tissue method (MLSRTM). The distribution of receptor BP ND obtained with Hypotime was consistent with previous autoradiography of postmortem brain tissue, with the highest values of BP ND recorded in the medial temporal lobe and decline of receptor availability with age. The values in the basal ganglia and cerebellum were negligible. The MLSRTM, in contrast, yielded lower BP ND in all regions and only weakly revealed the decline with age. Conclusion: The simple and computationally efficient Hypotime method gave reliable values of BP ND without the use of regression. The MLSRTM, on the other hand, appeared to be affected by the early disappearance of the radioligand from the circulation and the associated uncertain late presence of 11 C-WAY in the circulation.

Washout allometric reference method (WARM) for parametric analysis of [11C]PIB in human brains

“…Distinctive regions of high Θ values (i.e., close to T = Tomography duration) are indicative of a potential reference region, as previously demonstrated for the tracer [ 11 C]WAY-100635 ([ 11 C]WAY) (Hirvonen et al, 2007; Møller et al, 2009) where the cerebellar white matter served as the reference region.…”

“…A clear advantage of the H ypotime method was the production of washout indices in the form of Θ images with unit of time as an intermediate result (Møller et al, 2009). High Θ values (Θ > 1660 s relative to T = 1890 s) are indicative of the region's potential for service as reference.…”

“…In order to validate the cerebellar gray matter as a non-specifically binding region, we mapped the distribution of the washout index Θ image, which has unit of time, as defined for the H ypotime method (Møller et al, 2009). Distinctive regions of high Θ values (i.e., close to T = Tomography duration) are indicative of a potential reference region, as previously demonstrated for the tracer [ 11 C]WAY-100635 ([ 11 C]WAY) (Hirvonen et al, 2007; Møller et al, 2009) where the cerebellar white matter served as the reference region.…”

“…Three methodological problems complicate the correct quantification of binding of flow limited and rapidly metabolising tracers like [ 11 C]PIB in human brain (Møller et al, 2009). …”

“…Previous approaches to the analysis of wash-out of tracers included the early “Height-Over-Area” method of Zierler (1965) and the recent “Hypotime” method of Møller et al (2009), from both of which the current approach borrows, taking into account the methodological weaknesses discussed by Kanno and Uemura (1975). …”