Quantification of [¹¹C]yohimbine Binding to α₂ Adrenoceptors in Rat Brain in vivo

Abstract

We quantified the binding potentials (BPND) of [11C]yohimbine binding in rat brain to alpha-2 adrenoceptors to evaluate [11C]yohimbine as an in vivo marker of noradrenergic neurotransmission and to examine its sensitivity to the level of noradrenaline. Dual [11C]yohimbine dynamic positron emission tomography (PET) recordings were applied to five Sprague Dawley rats at baseline, followed by acute amphetamine administration (2 mg/kg) to induce elevation of the endogenous level of noradrenaline. The volume of distribution (VT) of [11C]yohimbine was obtained using Logan plot with arterial plasma input. Because alpha-2 adrenoceptors are distributed throughout the brain, the estimation of the BPND is complicated by the absence of an anatomic region of no displaceable binding. We used the Inhibition plot to acquire the reference volume, VND, from which we calculated the BPND. Acute pharmacological challenge with amphetamine induced a significant decline of [11C]yohimbine BPND of ~38% in all volumes of interest. The BPND was greatest in the thalamus and striatum, followed in descending order by, frontal cortex, pons, and cerebellum. The experimental data demonstrate that [11C]yohimbine binding is sensitive to a challenge known to increase the extracellular level of noradrenaline, which can benefit future PET investigations of pathologic conditions related to disrupted noradrenergic neurotransmission.

Quantitative Rodent Brain Receptor Imaging

“…Recent studies have focused on PET radiotracers for α2-adrenoreceptors such as [ 11 C]yohimbine [144] and [ 11 C]ORM-13070 [145]. [ 11 C]Yohimbine, for example, has been shown to be a surrogate marker of NA release in rats [146] and pigs [144] by showing a significant decrease in the V T in response to amphetamine challenge. For example, acute amphetamine injection of 2 mg/kg induced a BP ND change of~38 % in rats [146].…”

“…[ 11 C]Yohimbine, for example, has been shown to be a surrogate marker of NA release in rats [146] and pigs [144] by showing a significant decrease in the V T in response to amphetamine challenge. For example, acute amphetamine injection of 2 mg/kg induced a BP ND change of~38 % in rats [146]. However, the quantification of α2-adrenoreceptors and endogenous NA in rodent models with kinetic modeling still remains difficult due to the distribution of the receptors throughout the whole brain, leaving no appropriate reference region.…”

Application of cross-species PET imaging to assess neurotransmitter release in brain

“…For quantitative analysis in humans, a metabolite-corrected arterial input function may be required, although the corpus callosum was explored as a potential reference region (Nahimi et al 2015 ). Phan et al ( 2015 ) recently demonstrated that amphetamine also reduced [ 11 C]yohimbine binding in rats (Phan et al 2015 ).…”

“…Phan et al ( 2015 ) recently demonstrated that amphetamine also reduced [ 11 C]yohimbine binding in rats (Phan et al 2015 ).…”

How Relevant Are Imaging Findings in Animal Models of Movement Disorders to Human Disease?

“…Yohimbine is also a substrate of the p-glycoprotein (p-gp) (a member of the ABC-cassette family of blood brain barrier transporters) in rodents and does not cross into the brain unless the pump is inhibited. After p-gp inhibition, yohimbine can provide useful data in various rodent models [48,30]. Many other tracers also have variable substrate sensitivity to p-gp and other blood brain barrier transporters across different animal species, and this has to be taken into consideration when comparing human and animal model data [61,65].…”