Investigation of cross-species translatability of pharmacological MRI in awake nonhuman primate - a buprenorphine challenge study.

BACKGROUND: Pharmacological MRI (phMRI) is a neuroimaging technique where drug-induced hemodynamic responses can represent a pharmacodynamic biomarker to delineate underlying biological consequences of drug actions. In most preclinical studies, animals are anesthetized during image acquisition to minimize movement. However, it has been demonstrated anesthesia could attenuate basal neuronal activity, which can confound interpretation of drug-induced brain activation patterns. Significant efforts have been made to establish awake imaging in rodents and nonhuman primates (NHP). Whilst various platforms have been developed for imaging awake NHP, comparison and validation of phMRI data as translational biomarkers across species remain to be explored. METHODOLOGY: We have established an awake NHP imaging model that encompasses comprehensive acclimation procedures with a dedicated animal restrainer. Using a cerebral blood volume (CBV)-based phMRI approach, we have determined differential responses of brain activation elicited by the systemic administration of buprenorphine (0.03 mg/kg i.v.), a partial µ-opioid receptor agonist, in the same animal under awake and anesthetized conditions. Additionally, region-of-interest analyses were performed to determine regional drug-induced CBV time-course data and corresponding area-under-curve (AUC) values from brain areas with high density of µ-opioid receptors. PRINCIPAL FINDINGS: In awake NHPs, group-level analyses revealed buprenorphine significantly activated brain regions including, thalamus, striatum, frontal and cingulate cortices (paired t-test, versus saline vehicle, p<0.05, n = 4). This observation is strikingly consistent with µ-opioid receptor distribution depicted by [6-O-[(11)C]methyl]buprenorphine ([(11)C]BPN) positron emission tomography imaging study in baboons. Furthermore, our findings are consistent with previous buprenorphine phMRI studies in humans and conscious rats which collectively demonstrate the cross-species translatability of awake imaging. Conversely, no significant change in activated brain regions was found in the same animals imaged under the anesthetized condition. CONCLUSIONS: Our data highlight the utility and importance of awake NHP imaging as a translational imaging biomarker for drug research.

Biodistribution of different sized nanoparticles assessed by positron emission tomography: a general strategy for direct activation of metal oxide particles.

The extraordinary small size of NPs makes them difficult to detect and quantify once distributed in a material or biological system. We present a simple and straightforward method for the direct proton beam activation of synthetic or commercially available aluminum oxide NPs (Al2O3 NPs) via the 16O(p,α)13N nuclear reaction in order to assess their biological fate using positron emission tomography (PET). The radiolabeling of the NPs does not alter their surface or structural properties as demonstrated by TEM, DLS, and ζ-potential measurements. The incorporation of radioactive 13N atoms in the Al2O3 NPs allowed the study of the biodistribution of the metal oxide NPs in rats after intravenous administration via PET. Despite the short half-life of 13N (9.97 min), the accumulation of NPs in different organs could be measured during the first 68 min after administration. The percentage amount of radioactivity per organ was calculated to evaluate the relative amount of NPs per organ. This simple and robust activation strategy can be applied to any synthetic or commercially available metal oxide particle.

Tracing nanoparticles in vivo: a new general synthesis of positron emitting metal oxide nanoparticles by proton beam activation.

The synthesis of (18)F-labelled positron emitting NPs by direct irradiation of (18)O-enriched aluminum oxide NPs with 16 MeV protons is reported. Biodistribution studies of the labelled particles after intravenous administration were performed in male rats using positron emission tomography. The simple and general activation strategy can be applied to any in situ prepared core metal oxide particle for direct use or subsequent bio-compatible coating or encapsulation followed by functionalization.

Impaired functionality of reperfused brain tissue following short transient focal ischemia in rats.

Functional magnetic resonance imaging (fMRI) has been applied to study the consequences of transient focal ischemia on neuronal excitability in the rat brain. The experimental paradigm consisted of measuring the changes in local cerebral blood volume (CBV) induced by systemic infusion of the GABA(A) antagonist bicuculline after occlusion of the middle cerebral artery (MCA) for durations of 5, 15, 30 and 60 min using the intraluminal thread model. fMRI studies were carried out 60 min after successful reperfusion of the ischemic territory. Bicuculline-induced dynamic changes in local CBV were assessed in three brain regions: Parietal cortex, caudate putamen and thalamus. The measured CBV response was negatively correlated with the ischemia duration. Additionally, the three regions showed different vulnerability to the transient MCA occlusion, caudate being the most susceptible followed by parietal cortex and thalamus. The fMRI signals weakly correlated with basal CBF and CBV following reperfusion. Our results indicate that fMRI is a sensitive method to assess functional integrity of the brain. Activation maps allow to quantitatively assess the functionally compromized territory at an early stage following the ischemic event prior to the manifestation of pathomorphological changes.