Sergio Abad

Biodistribution of amino-functionalized diamond nanoparticles. In vivo studies based on 18F radionuclide emission.

Nanoparticles have been proposed for several biomedical applications; however, in vivo biodistribution studies to confirm their potential are scarce. Nanodiamonds are carbon nanoparticles that have been recently proposed as a promising biomaterial. In this study, we labeled nanodiamonds with (18)F to study their in vivo biodistribution by positron emission tomography. Moreover, the impact on the biodistribution of their kinetic particle size and of the surfactant agents has been evaluated. Radiolabeled diamond nanoparticles accumulated mainly in the lung, spleen, and liver and were excreted into the urinary tract. The addition of surfactant agents did not lead to significant changes in this pattern, with the exception of a slight reduction in the urinary excretion rate. On the other hand, after filtration of the radiolabeled diamond nanoparticles to remove those with a larger kinetic size, the uptake in the lung and spleen was completely inhibited and significantly reduced in the liver.

In Vivo Biodistribution of Amino-Functionalized Ceria Nanoparticles in Rats Using Positron Emission Tomography

A variety of nanoparticles have been proposed for several biomedical applications. To gauge the therapeutic potential of these nanoparticles, in vivo biodistribution is essential and mandatory. In the present study, ceria nanoparticles (5 nm average particle size) were labeled with (18)F to study their in vivo biodistribution in rats by positron emission tomography (PET). The (18)F isotope was anchored by reaction of N-succinimidyl 4-[(18)F]fluorobenzoate ((18)F-SFB) with a modified nanoparticle surface obtained by silylation with 3-aminopropylsilyl. Radiolabeled ceria nanoparticles accumulated mainly in lungs, spleen, and liver. Metabolic products of the radiolabeled nanoparticulate material were excreted into the urinary tract.

A molecular tool kit for the variable design of logic operations (NOR, INH, EnNOR)

A simple set of five components was used to design molecular logic gates based on phthalimide-sensitised Tb(III) luminescence, including the first report of an enabled NOR (EnNOR) gate.

Positron emission tomography with 11C-flumazenil in the rat shows preservation of binding sites during the acute phase after 2h-transient focal ischemia

BACKGROUND AND PURPOSE Positron emission tomography (PET) studies in humans have used (11)C-flumazenil (FMZ) to assess neuronal viability after stroke. Here we aimed to study whether (11)C-FMZ binding was sensitive to neuronal damage in the acute phase following ischemia/reperfusion in the rat brain. EXPERIMENTAL PROCEDURES Transient (2 h followed by reperfusion) and permanent intraluminal middle cerebral artery occlusion was carried out. (11)C-FMZ binding was studied by PET up to 24 h after the onset of ischemia. Tissue infarction was evaluated post-mortem at 24 h. Immunohistochemistry against a neuronal nuclei specific protein (NeuN) was performed to assess neuronal injury. RESULTS No decrease in (11)C-FMZ binding was detected in the ipsilateral cortex up to 24 h post-ischemia in the model of transient occlusion despite the fact that rats developed cortical and striatal infarction, and neuronal injury was clearly apparent at this time. In contrast, (11)C-FMZ binding was significantly depressed in the ipsilateral cortex at 24 h following permanent ischemia. CONCLUSIONS This finding evidences that (11)C-FMZ binding is not sensitive to neuronal damage on the acute phase of ischemia/reperfusion in the rat brain.

The effects of aging on dopaminergic neurotransmission: a microPET study of [11C]-raclopride binding in the aged rodent brain.

Rodent models are frequently used in aging research to investigate biochemical age effects and aid in the development of therapies for pathological and non-pathological age-related degenerative processes. In order to validate the use of animal models in aging research and pave the way for longitudinal intervention-based animal studies, the consistency of cerebral aging processes across species needs to be evaluated. The dopaminergic system seems particularly susceptible to the aging process, and one of the most consistent findings in human brain aging research is a decline in striatal D2-like receptor (D2R) availability, quantifiable by positron emission tomography (PET) imaging. In this study, we aimed to assess whether similar age effects can be discerned in rat brains, using in vivo molecular imaging with the radioactive compound [(11)C]-raclopride. We observed a robust decline in striatal [(11)C]-raclopride uptake in the aged rats in comparison to the young control group, comprising a 41% decrement in striatal binding potential. In accordance with human studies, these results indicate that substantial reductions in D2R availability can be measured in the aged striatal complex. Our findings suggest that rat and human brains exhibit similar biochemical alterations with age in the striatal dopaminergic system, providing support for the pertinence of rodent models in aging research.

Intramolecular electron transfer in diastereomeric naphthalene–amine dyads: a fluorescence and laser flash photolysis study

Two dyads containing a naphthalene-like chromophore linked to a pyrrolidine-derived moiety, namely (S,S)- and (R,S)-NPX-PYR, have been synthesised by esterification of (S)- or (R)-naproxen (NPX) with (S)-N-methyl-2-pyrrolidinemethanol (PYR) and submitted to photophysical studies (steady-state and time-resolved fluorescence, as well as laser flash photolysis). The emission spectra of the dyads in acetonitrile were characterised by a typical band centred at 350 nm, identical to that of the reference compound (S)-NPX. However the intensities were clearly different, revealing a significant intramolecular quenching in the dyads, as well as a remarkable stereodifferentiation (factor of 1.6). Accordingly, the fluorescence lifetimes of the two dyads were different from each other and markedly shorter than that of (S)-NPX. The quenching mechanism is intramolecular electron transfer, that is thermodynamically favoured. Exciplex formation, that is nearly thermoneutral, does not compete efficiently. The electron transfer rate constants for (S,S)- and (R,S)-(NPX-PYR) were 1.8 x 10(8) and 2.8 x 10(8) s(-1), respectively. By contrast, no significant intramolecular quenching was observed for the excited triplet states (lambda(max)= 440 nm), generated by laser flash photolysis; this is in agreement with the fact that intramolecular electron transfer is thermodynamically disfavoured, due to the lower energy of excited triplets.

In vivo molecular imaging of the GABA/benzodiazepine receptor complex in the aged rat brain

The GABA-ergic system, known to regulate neural tissue genesis during cortical development, has been postulated to play a role in cerebral aging processes. Using in vivo molecular imaging and voxel-wise quantification, we aimed to assess the effects of aging on the benzodiazepine (BDZ) recognition site of the GABA(A) receptor. To visualize BDZ site availability, [(11)C]-flumazenil microPET acquisitions were conducted in young and old rats. The data were analyzed and region of interest analyses were applied to validate the voxel-wise approach. We observed decreased [(11)C]-flumazenil binding in the aged rat brains in comparison with the young control group. More specifically, clusters of reduced radioligand uptake were detected in the bilateral hippocampus, cerebellum, midbrain, and bilateral frontal and parieto-occipital cortex. Our results support the pertinence of voxel-wise quantification in the analysis of microPET data. Moreover, these findings indicate that the aging process involves declines in neural BDZ recognition site availability, proposed to reflect alterations in GABA(A) receptor subunit polypeptide expression.

Positron Emission Tomographic Imaging of the Cannabinoid Type 1 Receptor System with ( 11 C)OMAR (( 11 C)JHU75528): Improvements in Image Quantification Using Wild-Type and Knockout Mice

In this study, we assessed the feasibility of using positron emission tomography (PET) and the tracer [¹¹C]OMAR ([¹¹C]JHU75528), an analogue of rimonabant, to study the brain cannabinoid type 1 (CB1) receptor system. Wild-type (WT) and CB1 knockout (KO) animals were imaged at baseline and after pretreatment with blocking doses of rimonabant. Brain uptake in WT animals was higher (50%) than in KO animals in baseline conditions. After pretreatment with rimonabant, WT uptake lowered to the level of KO animals. The results of this study support the feasibility of using PET with the radiotracer [¹¹C]JHU75528 to image the brain CB1 receptor system in mice. In addition, this methodology can be used to assess the effect of new drugs in preclinical studies using genetically manipulated animals.

Rapid and high-yielding cysteine labelling of peptides with N-succinimidyl 4-[18F]fluorobenzoate.

Fast cysteine labelling of peptides promoted by an adjacent arginine has been observed with a standard labelling agent specific for amines, N-succinimidyl 4-[(18)F]fluorobenzoate.

[11C]-DASB microPET imaging in the aged rat: Frontal and meso-thalamic increases in serotonin transporter binding

Whereas molecular imaging studies in the aging human brain have predominantly demonstrated reductions in serotonin transporter (5-HTT) availability, the majority of the rodent studies, using autoradiographic methods, report increases in neural 5-HTT levels with age. To our knowledge, however, no previous rodent studies have assessed this topic in vivo, and therefore it remains unclear whether this discrepancy arises from methodological or inter-species differences. We performed an [(11)C]-DASB microPET study to evaluate the effects of aging on 5-HTT availability in the rat brain. To generate binding potential estimates, quantitative tracer kinetic modeling was applied using the simplified reference tissue model. A global increase in whole-brain [(11)C]-DASB binding potential was observed in the aged rats in comparison to the control group. More specifically, regional analyses revealed a highly significant increase in 5-HTT binding in the medial frontal cortex, and more modest increments in the midbrain/thalamus. Our results suggest that the frontal cortex represents a site of robust age-related alterations in the rat serotonergic system, and stress the need for further research assessing this topic in the human frontal cortex. Moreover, these findings suggest that the reported discrepancies between rodent and human data may reflect a divergence in the aging processes affecting human and rat serotonergic terminals.