A database of [18F]-altanserin binding to 5-HT2A receptors in normal volunteers: normative data and relationship to physiological and demographic variables
Introduction
Molecular brain imaging is one of the most rapidly growing fields in neuroscience enabling mapping of cerebral functions such as regional glucose metabolism, neuroreceptor density, or changes in neurotransmitter levels. The use of brain maps and large databases of normative imaging data is becoming increasingly prevalent, particularly to aid experimental design, interpretation of results, and in the comparison of data from different imaging modalities. Laboratories are starting initiatives of comparing data across research groups and establishing databases with the purpose of arriving at more general conclusions of the functional contributions in different parts of the human brain Mazziotta et al., 2001, Roland et al., 2001. Databases for structural (Evans et al., 1992), resting cerebral glucose uptake (Willis et al., 2002), and cerebral blood flow activation (Fox et al., 1994) have been described, but the number of large published databases for neuroreceptors is limited. Until now, larger positron emission tomography (PET) databases of normative data (here arbitrarily defined as n > 30) include the striatal dopamine D2 receptor (n = 54), (Pohjalainen et al., 1998), (n = 42) (Wang et al., 1996), (n = 32) (Antonini et al., 1993), the extra-striatal D2 receptor (n = 37) (Kaasinen et al., 2002), the serotonin (5-hydroxytryptamine, or 5-HT) 5-HT1A receptor (n = 61), (Rabiner et al., 2002), the muscarinic M2 receptor (n = 35), (Podruchny et al., 2003), and the muscarinic acetylcholinergic receptor (n = 37), (Yoshida et al., 2000). In this paper, we describe a large normative database of the cerebral 5-HT2A receptor binding.
Alterations in serotonergic neurotransmission have been implicated in many human disorders such as anxiety, depression, psychosis, migraine, as well as in normal human functions such as sleep, sexual activity, and appetite (see Naughton et al., 2000). Seven families of serotonin receptors have been identified and designated the name 5-HT1 to 5-HT7 by their molecular and biological characteristics. The seven families have so far been subdivided into 15 subtypes, a number, which is likely to increase further. Along with the 5-HT1A receptor and also the 5-HT reuptake site, the 5-HT2A receptor is a frequently targeted site of action for antipsychotic and antidepressant drugs, and it has been well characterized physiologically. The 5-HT2A receptor is a postsynaptically located G-protein-coupled receptor that mediates some actions of synaptic 5-HT (Ronken and Olivier, 1997). The 5-HT2A receptor distribution in the brain is heterogeneous with high levels in cortical areas and intermediate concentrations in limbic areas and the basal ganglia. In addition, the cerebellum is considered to contain negligible levels of 5-HT2A receptors (Pazos et al., 1987), which is the reason why all PET studies so far have used this region as a reference region.
PET enables the in vivo imaging of the regional distribution of 5-HT2A receptors in the human brain. Currently, there are three PET ligands that have been used in clinical studies of 5HT2A receptors: [11C]-MDL100907, [18F]-setoperone, and [18F]-altanserin. In this database [18F]-altanserin, a 4-fluorobenzoyl-piperidine derivative was used. Quantification of [18F]-altanserin binding to 5-HT2A receptors following a bolus injection of the tracer has been done either from a kinetic analysis with metabolite-corrected plasma input Biver et al., 1994, Biver et al., 1996, Liptrot et al., 2004 or from a Logan analysis Meltzer et al., 1998, Rosier et al., 1996. Smith et al. (1998) compared the kinetic modeling (two- and three-tissue compartments) and Logan analysis and demonstrated a larger distribution volume (DV) ratio test–retest difference for the kinetic method. In general, the Logan graphical analysis is more stable than the nonlinear least-squares curve-fitting methods (Logan et al., 1990). An alternative approach is to determine the binding potential (BMAX/Kd) or DV for [18F]-altanserin with the bolus infusion approach Pinborg et al., 2003, Van Dyck et al., 2000a based on the presence of a radiotracer steady state in both brain tissue and plasma. The advantage of the latter method is that the contribution from radiolabeled lipophilic metabolites of [18F]-altanserin can be subtracted directly, provided that a suitable reference region void of receptors can be identified.
Previous PET studies with [18F]-altanserin Biver et al., 1994, Biver et al., 1996, Forutan et al., 2002, Meltzer et al., 1998, Moses et al., 2000, Pinborg et al., 2003, Price et al., 2001, Rosier et al., 1996, Sadzot et al., 1995, Sheline et al., 2002, Smith et al., 1998, Van Dyck et al., 2000a, Van Dyck et al., 2000b have described the 5-HT2A receptor distribution in a limited number of healthy subjects (range n = 5-22 subjects) with narrow age intervals. The same is true for [11C]-MDL100907 and [18F]-setoperone PET studies, where the largest study included 29 subjects (Meyer et al., 2003). One study has indicated that 5-HT2A binding of [18F]-altanserin is gender-related (Biver et al., 1996), and three studies have uniformly shown that age is negatively correlated with 5HT2A binding Meltzer et al., 1998, Rosier et al., 1996, Sheline et al., 2002. Recently, [18F]-altanserin and PET was used to demonstrate dysfunction in the 5-HT2A function in depressed patients Biver et al., 1997, Larisch et al., 2001, Meltzer et al., 1999a, patients with obsessive-compulsive disorder (own unpublished data), and in patients with anorexia nervosa (Frank et al., 2002) and bulimia (Kaye et al., 2001). In all of the studies, a considerable inter-subject variability in 5-HT2A binding of [18F]-altanserin has been observed, which presumably reflects the net effects of biological, demographic, and methodological variables. In this study, we report the results from a database of in vivo 5-HT2A receptor binding of [18F]-altanserin in 52 healthy subjects, collected over 3 years, and examine the relationship of binding to methodological and subject-specific variables. We investigated both methodological aspects and whether the cerebral 5-HT2A binding, as defined by the binding of [18F]-altanserin, differed between gender, as well as the possible correlations between 5-HT2A receptor binding and age and body mass index (BMI).
Section snippets
Subjects
Fifty-four healthy volunteers were included in the study; 23 women and 31 men, with a mean age of 46 years (range: 21–79). The relative age distribution for the women were 47.4 ± 19.6 years (mean ± SD) and the age distribution for the men were 45.4 ± 20.1 years. For both sexes, the age range was 21–79 years. The subjects were included from ongoing clinical research studies. The subjects were largely normal-weighted with a BMI of 24.8 ± 3.7 (mean ± SD). None of the subjects had a history of
Equilibrium model assumptions
The equilibrium method requires that steady state is present in both blood and brain tissue (Lassen, 1992). When steady state is present, the DV can be calculated as the ratio of tissue radiotracer concentration to plasma radiotracer concentration. In receptor studies, the DV of a region of interest (DVROI) represents the sum of the specifically bound DV (DV3) and the nonspecifically bound (DV2). DV2 represents radiolabeled ligand and potential metabolites in the brain, free or nonspecifically
Normative [18F]-altanserin PET and blood data
The regional partial volume-corrected DV3′ values are reported in decreasing order in Table 1. The cortical values of DV3′ differed only slightly.
At the time of investigation (approximately 140 min after [18F]-altanserin infusion started), DV2 in terms of CCerebellum/CPlasma, was 2.02 ± 0.62 (mean ± SD). A positive correlation between DV2 in terms of cerebellar binding and age was found (see Fig. 2) as well as a significant gender effect (R = 0.644, P < 0.0125). Women had a significantly higher
Discussion
In this paper, we report the so far largest database of human subjects for in vivo characterization of the cerebral serotonin 5-HT2A receptors. In the following, the relation between binding parameters and several methodological and demographic variables is discussed.
Acknowledgements
The authors wish to thank Karin Stahr, Mads Dyrholm, Dorthe Givard, and the staff at the PET Centre at Rigshospitalet, Copenhagen, for their assistance. The Danish Health Research Council, the 1991 Pharmacy Foundation, the Health Insurance Fund, the Lundbeck Foundation, the EU fifth framework programme (QLK6-CT-2000-00 502), Lægernes forsikringsforening af 1891, and Fonden af 1870 are thanked for funding the project. In addition, the John and Birthe Meyer Foundation is thanked for the donation
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