Validation of [¹¹C]ORM‐13070 as a PET tracer for alpha_2c‐adrenoceptors in the human brain

Abstract

This study explored the use of the α2C -adrenoceptor PET tracer [(11) C]ORM-13070 to monitor α2C -AR occupancy in the human brain. The subtype-nonselective α2 -AR antagonist atipamezole was administered to eight healthy volunteer subjects to determine its efficacy and potency (Emax and EC50 ) at inhibiting tracer uptake. We also explored whether the tracer could reveal changes in the synaptic concentrations of endogenous noradrenaline in the brain, in response to several pharmacological and sensory challenge conditions. We assessed occupancy from the bound-to-free ratio measured during 5-30 min post injection. Based on extrapolation of one-site binding, the maximal extent of inhibition of striatal [(11) C]ORM-13070 uptake (Emax ) achievable by atipamezole was 78% (95% CI 69-87%) in the caudate nucleus and 65% (53-77%) in the putamen. The EC50 estimates of atipamezole (1.6 and 2.5 ng/ml, respectively) were in agreement with the drug's affinity to α2C -ARs. These findings represent clear support for the use of [(11) C]ORM-13070 for monitoring drug occupancy of α2C -ARs in the living human brain. Three of the employed noradrenaline challenges were associated with small, approximately 10-16% average reductions in tracer uptake in the dorsal striatum (atomoxetine, ketamine, and the cold pressor test; P < 0.05 for all), but insulin-induced hypoglycemia did not affect tracer uptake. The tracer is suitable for studying central nervous system receptor occupancy by α2C -AR ligands in human subjects. [(11) C]ORM-13070 also holds potential as a tool for in vivo monitoring of synaptic concentrations of noradrenaline, but this remains to be further evaluated in future studies.

Disease-modifying effect of atipamezole in a model of post-traumatic epilepsy

“…Our supplementary studies made an attempt to understand the mechanisms of favourable recovery-enhancing effects of atipamezole. ATI, a selective 2-adrenergic antagonist with a high 2/1 adrenoceptor selectivity ratio, does not display differential affinity for 2-adrenoceptor subtypes A, B, or C in the rodent or human brain (Haapalinna et al, 1997;Lehto et al, 2015;Virtanen et al, 1989). The 2-adrenergic receptors are located in adrenergic, serotonergic, and dopaminergic nerve terminals (Flügge et al, 2003;Gobert et al, 1998).…”

Detecting a dexmedetomidine-evoked reduction of noradrenaline release in the human brain with the alpha2C-adrenoceptor PET ligand [11C]ORM-13070

“…Dexmedetomidine infusion causes a decrease in blood pressure and heart rate, which is thought to be the result of activation of autoinhibitory a 2A -ARs in the CNS, causing decreased sympathetic nervous system activity. Marked reductions in the concentrations of both noradrenaline (about 75%) and adrenaline in peripheral venous plasma have been reported in humans at plasma dexmedetomidine concentrations of 0.5-0.6 ng/ml (Ebert et al, 2000;Snapir et al, 2006 (Lehto et al, 2015b;Finnema et al, 2014). Strong evidence in support of the tracer's sensitivity to increased synaptic noradrenaline in human subjects was gained in our previous study with different pharmacological and physiological challenges (Lehto et al, 2015c).…”

“…When PET tracer binding is estimated with tissue ratios following a bolus injection, decreased regional CBF could affect binding estimates by decreasing the efflux (k 2 ) from the free tissue compartment. With [ 11 C]ORM-13070, however, we have previously demonstrated a lack of effect on striatal binding estimates (Lehto et al, 2015b) with insulin-induced hypoglycaemia, which has been shown to increase striatal CBF with both PET and pASL-MRI (Arbel aez et al 2013). fMRI and FDG-PET experiments have suggested decreased thalamic regional CBF in response to dexmedetomidine (Akeju et al, 2014) (Lå ngsj€ o et al 2012), but these results were obtained with anesthetic dexmedetetomidine concentrations up to 2.25 ng/ml.…”

“…Marked reductions in the concentrations of both noradrenaline (about 75%) and adrenaline in peripheral venous plasma have been reported in humans at plasma dexmedetomidine concentrations of 0.5-0.6 ng/ml (Ebert et al, 2000;Snapir et al, 2006). The PET tracer [ 11 C]ORM-13070 has been validated as a cross-species a 2C -AR radioligand, useful for receptor occupancy analysis in clinical drug development (Lehto et al, 2015b;Finnema et al, 2014). Strong evidence in support of the tracer's sensitivity to increased synaptic noradrenaline in human subjects was gained in our previous study with different pharmacological and physiological challenges (Lehto et al, 2015c).…”

Application of the PET ligand [11C]ORM-13070 to examine receptor occupancy by the α2C-adrenoceptor antagonist ORM-12741: translational validation of target engagement in rat and human brain&nbsp;

“…anxiety) side-effects that are commonly observed with subtype nonselective α 2 -AR antagonists(12,13). [ 11 C]ORM-13070 has previously been validated as a selective PET ligand for assessing α 2C -AR expression and occupancy in rat (4) and human brain(7). The current results extend and support these previous ndings, con rming that[ 11 C]ORM-13070 shows similar regional distribution patterns in rat and human brain, with the most intense signal in the striatum.…”