Simplified quantification of 5-HT2A receptors in the human brain with [11C]MDL 100,907 PET and non-invasive kinetic analyses
Introduction
The G-protein coupled serotonin receptor subtype 2A (5-HT2A receptor) modulates cortical GABAergic, glutamatergic and dopaminergic neurotransmission by various mechanisms and interactions. A proper balance of 5-HT2A receptor activity at inhibitory and excitatory neurons appears to be required for normal neuronal functioning (Leysen, 2004). Consequently, the 5-HT2A receptor has been implicated in various physiological functions and pathological conditions, including schizophrenia, major depression, anxiety and sleep disorders (Jones and Blackburn, 2002, Landolt and Wehrle, 2009). Positron emission tomography (PET) allows a quantification of 5-HT2A receptor availability in the living human brain, and thus provides an invaluable technique for the investigation of the 5-HT2A receptor in different subject and patient populations and its interventional interference. Various 5-HT2A receptor ligands have been proposed as PET radiopharmaceutical for 5-HT2A receptor quantification, most notably [11C]N-methylspiperone ([11C]NMSP) (Wong et al., 1984), [18F]altanserin (Biver et al., 1994), [18F]setoperone (Blin et al., 1988) and [11C]MDL 100,907 (Lundkvist et al., 1996). Compared with the former, [11C]MDL 100,907 appears to be the most promising 5-HT2A radiopharmaceutical because of its high brain uptake with high specific-to-non-specific uptake contrast, prototypical 5-HT2A receptor selectivity and absence of blood–brain-barrier penetrating radiolabelled metabolites interfering with 5-HT2A receptor quantification.
Several methods of analysis have been considered for [11C]MDL 100,907 PET quantification so far: The theoretically best validated approach is the use of a pharmacokinetic two-tissue compartment model (2TCM) analysis with an arterial plasma input function, which yields significantly better fits to kinetic [11C]MDL 100,907 data than an one-tissue compartment model (1TCM), especially in regions with no or little 5-HT2A receptor binding (Ito et al., 1998, Watabe et al., 2000a, Hinz et al., 2007). The total volume of distribution (VT) and the binding potential relative to non-displaceable radioligand in tissue (BPND) (Innis et al., 2007) were proposed as outcome measures related to 5-HT2A receptor availability. The 2TCM has also been successfully used recently in praxi to demonstrate increased 5-HT2A receptor binding in patients recovered from depression (Bhagwagar et al., 2006). As a simplification, albeit still relying on arterial blood samples, various groups have also used Logan's graphical analyses (GA) (Logan et al., 1990) to estimate VT or BPND (Ito et al., 1998, Watabe et al., 2000a, Ichise et al., 2002, Kakiuchi et al., 2000). Although 2TCM and GA agree well, simulations studies suggest a negative VT bias in GA in presence of high noise levels (Watabe et al., 2000a, Ichise et al., 2002). This is in line with the well-known noise-dependent bias of GA (Carson et al., 1993, Slifstein and Laruelle, 2000). In addition, however, Ichise et al. (2002) also noted a small negative VT bias (about 7%) at relatively low noise, which can be attributed to difficulties in identifying the linear part of the GA plot (its slope being equal to VT). This appears to be particularly problematic in the case of the slow kinetics of [11C]MDL 100,907, where the asymptomatically linear portion of the GA occurs at relatively late times (Ichise et al., 2002).
The reliance of the kinetic analyses (1TCM, 2TCM and GA) on an arterial plasma input function represents a substantial drawback in regard of a broad application of this technique in basic and applied neurosciences. On one hand, arterial blood sampling and plasma analyses are invasive, labour and cost intensive. On the other, they can be a major source of error in quantitative PET analyses. Thus, the application of entirely non-invasive reference tissue analyses, which avoid the need for an arterial input function, is of great interest and the crucial question, whether there is a valid reference region devoid of detectable specific binding, has been a matter of debate. In their initial study, Lundkvist et al. (1996) found no effect of ketanserin preblocking or displacement on [11C]MDL 100,907 binding in the cerebellum of a cynomolgus monkey, which suggested that the cerebellum is a valid reference region. However, Watabe and colleagues noted that there is a small fraction of displaceable [11C]MDL 100,907 binding in cerebellum in preblocking experiments in rhesus monkeys (Watabe et al., 2000a). Hinz et al. (2007) performed preblocking experiments in humans using a clinical dose of the antidepressant drug mirtazapine (30 mg), which has a nanomolar affinity for 5-HT2A receptors (Anttila and Leinonen, 2001). They found a substantial and fairly homogenous 5-HT2A occupancy in all regions except the cerebellum, in which mirtazapine exhibited no significant effect on [11C]MDL 100,907 uptake. In line with this, the cerebellum was also found to be virtually devoid of 5-HT2A receptors on human post mortem autoradiography (Hall et al., 2000).
However the use of reference tissue analyses for [11C]MDL 100,907 PET quantification has not been appropriately validated so far, although different reference tissue approaches have been used in [11C]MDL 100,907 studies in humans (Talvik-Lotfi et al., 2000, Turkheimer et al., 2003, Perani et al., 2008) and rats (Hirani et al., 2003). Although only in abstract form, the work of Watabe et al. (2000b) requires particular attention: They proposed a reference tissue model assuming a 1TCM and 2TCM configuration for the regions of interest and the reference region cerebellum, respectively. This model performed well on simulated [11C]MDL 100,907 data but no actual experimental data were given. Hinz and colleagues tested this model on their human [11C]MDL 100,907 data but no reliable parameter and occupancy estimates could be obtained (Hinz et al., 2007) probably because of too many free parameters in this particular reference tissue model configuration (two rate constants for the target region and four rate constants in the reference region) and the very slow kinetics of [11C]MDL 100,907 in tissue.
Thus, the purpose of the present study was to evaluate the use of standard reference tissue analyses for quantification of 5-HT2A receptor availability using [11C]MDL 100,907 PET. We re-analyzed the paired human [11C]MDL 100,907 PET studies with and without mirtazapine pre-treatment previously published by Hinz et al. (2007) to evaluate the use of the following widely used kinetic analysis methods: the simplified reference tissue model (Lammertsma and Hume, 1996), the two-step simplified reference tissue model (Wu and Carson, 2002), the multi-linear reference tissue model (MRTM) and the multi-linear reference tissue model 2 (MRTM2) (Ichise et al., 2003) and a non-invasive graphical analysis (NIGA) (Logan et al., 1996). In addition, we considered a simple late [11C]MDL 100,907 tissue activity concentration ratio as a surrogate marker of receptor availability and the use of NIGA for generation of quantitative 5-HT2A maps.
Section snippets
Subjects
In the present study we re-analyzed the data of a previous [11C]MDL 100,907 PET study which included arterial blood sampling and comprehensive metabolite analyses for input function measurement and subsequent tracer kinetic modelling in healthy normal volunteers (Hinz et al., 2007). Five normal volunteers (four males aged 37, 55, 62 and 63 years and one female of 59 years) were included after giving written informed consent and careful screening to exclude any relevant medical, psychiatric or
Simplified reference tissue models and multilinear reference tissue models
Representative TACs are shown in Figs. 1A and B under baseline conditions and after blockade with 30 mg mirtazapine, respectively. Note the pronounced effect of mirtazapine on [11C]MDL 100,907 uptake in cortical and subcortical target regions, while cerebellar uptake remained unaffected which underlines the validity of the cerebellum as a reference region (Hinz et al., 2007).
SRTM and MRTM yielded reasonable fits to regional TAC in most instances. All data points were included into MRTM analyses
Discussion
The 5-HT2A receptor antagonist [11C]MDL 100,907 holds great promise as a PET radiopharmaceutical for in vivo 5-HT2A receptor quantification. It binds to 5-HT2A receptor with high affinity (Ki = 0.2 nM) und high selectivity, rendering [11C]MDL 100,907 a prototypical 5-HT2A receptor antagonist. In contrast, other 5-HT2A PET tracers like [11C]NMSP and [18F]setoperone also exhibit significant binding to dopamine receptors (Lyon et al., 1986, Blin et al., 1988). Furthermore, [11C]MDL 100,907
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