[show abstract][hide abstract] ABSTRACT: Scanning properties and analytic methodology of the 5-HT2A receptor-selective positron emission tomography (PET) tracer 11C-MDL100907 have been partially characterised in previous reports. We present an extended characterisation in healthy human subjects.
64 11C-MDL100907 PET scans with metabolite-corrected arterial input function were performed in 39 healthy adults (18-55 years). 12 subjects were scanned twice (duration 150 min) to provide data on plasma analysis, model order estimation, and stability and test-retest characteristics of outcome measures. All other scans were 90 min duration. 3 subjects completed scanning at baseline and following 5-HT2A receptor antagonist medication (risperidone or ciproheptadine) to provide definitive data on the suitability of the cerebellum as reference region. 10 subjects were scanned under reduced 5-HT and control conditions using rapid tryptophan depletion to investigate vulnerability to competition with endogenous 5-HT. 13 subjects were scanned as controls in clinical protocols. Pooled data were used to analyse the relationship between tracer injected mass and receptor occupancy, and age-related decline in 5-HT2A receptors.
Optimum analytic method was a 2-tissue compartment model with arterial input function. However, basis function implementation of SRTM may be suitable for measuring between-group differences non-invasively and warrants further investigation. Scan duration of 90 min achieved stable outcome measures in all cortical regions except orbitofrontal which required 120 min. Binding potential (BPP and BPND) test-retest variability was very good (7-11%) in neocortical regions other than orbitofrontal, and moderately good (14-20%) in orbitofrontal cortex and medial temporal lobe. Saturation occupancy of 5-HT2A receptors by risperidone validates the use of the cerebellum as a region devoid of specific binding for the purposes of PET. We advocate a mass limit of 4.6 μg to remain below 5% receptor occupancy. 11C-MDL100907 specific binding is not vulnerable to competition with endogenous 5-HT in humans. Paradoxical decreases in BPND were found in right prefrontal cortex following reduced 5-HT, possibly representing receptor internalisation. Mean age-related decline in brain 5-HT2A receptors was 14.0±5.0% per decade, and higher in prefrontal regions.
Our data confirm and extend support for 11C-MDL100907 as a PET tracer with very favourable properties for quantifying 5-HT2A receptors in the human brain.
[show abstract][hide abstract] ABSTRACT: [11C]PHNO is a recently introduced agonist to image DA D2-like receptors with Positron Emission Tomography (PET). In cats and humans, [11C]PHNO revealed an atypical distribution compared to radiolabeled D2-like antagonists (such as [11C]raclopride) or other D2-like agonists (such as [11C]NPA), as it displayed unusual high binding in the globus pallidus (GP). The goal of this study was to assess the pharmacological nature of the binding of [11C]PHNO in the GP in nonhuman primates. As previously reported in humans, [11C]PHNO equilibrium specific to nonspecific equilibrium partition coefficients (V3'') in baboons was much higher in GP (3.88 +/- 1.15) than in the dorsal striatum (DST, 2.07 +/- 0.43), whereas the reverse was true for [11C]raclopride (1.48 +/- 0.41 in GP, 2.56 +/- 0.91 in DST) and [11C]NPA (0.87 +/- 0.19 in GP, 1.02 +/- 0.13 in DST). Administration of unlabeled raclopride resulted in similar reductions of [11C] PHNO V3'' and [11C]raclopride V3'' in both the GP and the DST. This observation demonstrated that the [11C]PHNO binding in the GP was specific to D2-like receptors. To evaluate the respective contribution of D3 and D2 receptors to the binding potential (BP) of [11C]PHNO and [11C]raclopride, experiments were carried out with the selective D3 partial agonist 1-(4(2-Napthoylamino)butyl)-4-(2-methoxyphenyl)-1A-piperazine HCL (BP897). BP897 reduced [11C]raclopride V3'' by 29% +/- 9%, 19% +/- 8%, and 10% +/- 7% in GP, VST, and DST, respectively, a result consistent with expectation from postmortem studies (D3/D2 ratio in GP > VST > DST). BP897 reduced [11C]PHNO V3'' by 57% +/- 11%, 30% +/- 11%, and 13% +/- 8% in GP, VST, and DST, respectively, indicating that the D3 receptor contribution to [11C]PHNO signal is higher than that of [11C]raclopride. From these experiments we conclude that [11C]PHNO is a D3 preferring agonist, and that this property explains the high GP signal not observed with [11C]raclopride or [11C]NPA. This property might contribute to its higher vulnerability to endogenous DA compared to [11C]raclopride and [11C]NPA.
[show abstract][hide abstract] ABSTRACT: Dopamine D2 receptors are configured in interconvertible states of high (D(2 high)) or low (D(2 low)) affinity for agonists. The in vivo proportion of sites in high-affinity state remains poorly documented. Previous studies have established the D2 agonist [11C]N-propyl-norapomorphine (NPA) as a suitable positron emission tomography radiotracer for imaging D(2 high) in the living brain. To elucidate the proportion of D2 receptors configured in D(2 high) states in vivo, imaging studies were conducted in three baboons with both [11C]NPA and the D2 receptor antagonist [11C]raclopride. These studies were performed under noncarrier- and carrier-added conditions, to compare the Bmax of [11C]NPA and [11C]raclopride in the same animals. [11C]raclopride in vivo KD and Bmax were 1.59 +/- 0.28 nM (n = 3) and 27.3 +/- 3.9 nM (n = 3), respectively. The in vivo KD of [11C]NPA was 0.16 +/- 0.01 nM (n = 3), consistent with its affinity for D(2 high) reported in vitro. The maximal density of sites for [11C]NPA was 21.6 +/- 2.8 nM (n = 3), i.e., 79% of the [11C]raclopride Bmax. This result suggested that 79% of D2 receptors are configured as D(2 high) in vivo. This large proportion of D(2 high) sites might explain the vulnerability of D2 radiotracers to competition by endogenous dopamine, and is consistent with a previous report that the in vivo binding of agonist radiotracer [11C]NPA is more vulnerable to competition by endogenous dopamine than that of antagonist radiotracer [11C]raclopride.
Journal of Pharmacology and Experimental Therapeutics 11/2005; 315(1):80-90. · 3.89 Impact Factor