Evaluation of \u3csup\u3e18\u3c/sup\u3eF-IAM6067 as a sigma-1 receptor PET tracer for neurodegeneration in vivo in rodents and in human tissue

© The author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions. The sigma 1 receptor (S1R) is widely expressed in the CNS and is mainly located on the endoplasmic reticulum. The S1R is involved in the regulation of many neurotransmission systems and, indirectly, in neurodegenerative diseases. The S1R may therefore represent an interesting neuronal biomarker in neurodegenerative diseases such as Parkinson\u27s (PD) or Alzheimer\u27s diseases (AD). Here we present the characterisation of the S1R-specific 18F-labelled tracer 18F-IAM6067 in two animal models and in human brain tissue. Methods: Wistar rats were used for PET-CT imaging (60 min dynamic acquisition) and metabolite analysis (1, 2, 5, 10, 20, 60 min post-injection). To verify in vivo selectivity, haloperidol, BD1047 (S1R ligand), CM398 (S2R ligand) and SB206553 (5HT2B/C antagonist) were administrated for pre-saturation studies. Excitotoxic lesions induced by intra-striatal injection of AMPA were also imaged by 18F-IAM6067 PET-CT to test the sensitivity of the methods in a well-established model of neuronal loss. Tracer brain uptake was also verified by autoradiography in rats and in a mouse model of PD (intrastriatal 6-hydroxydopamine (6-OHDA) unilateral lesion). Finally, human cortical binding was investigated by autoradiography in three groups of subjects (control subjects with Braak ≤2, and AD patients, Braak \u3e2 & ≤4 and Braak \u3e4 stages). Results: We demonstrate that despite rapid peripheral metabolism of 18F-IAM6067, radiolabelled metabolites were hardly detected in brain samples. Brain uptake of 18F-IAM6067 showed differences in S1R anatomical distribution, namely from high to low uptake: pons-raphe, thalamus medio-dorsal, substantia nigra, hypothalamus, cerebellum, cortical areas and striatum. Pre-saturation studies showed 79-90% blockade of the binding in all areas of the brain indicated above except with the 5HT2B/C antagonist SB206553 and S2R ligand CM398 which induced no significant blockade, indicating good specificity of 18F-IAM6067 for S1Rs. No difference between ipsi- and contralateral sides of the brain in the mouse model of PD was detected. AMPA lesion induced a significant 69% decrease in 18F-IAM6067 uptake in the globus pallidus matching the neuronal loss as measured by NeuN, but only a trend to decrease (-16%) in the caudate putamen despite a significant 91% decrease in neuronal count. Moreover, no difference in the human cortical binding was shown between AD groups and controls. Conclusion: This work shows that 18F-IAM6067 is a specific and selective S1R radiotracer. The absence or small changes in S1R detected here in animal models and human tissue warrants further investigations and suggests that S1R might not be the anticipated ideal biomarker for neuronal loss in neurodegenerative diseases such as AD and PD

Marine epibiosis. II. Reduced fouling on Polysyncraton lacazei (Didemnidae, Tunicata) and proposal of an antifouling potential index

Polysyncraton lacazei is a colonial tunicate (family didemnidae) living in the NW-mediterranean rocky sublitoral. A thorough scanning of numerous colonies revealed that in spite of an apparently heavy local fouling pressure only one fouling species — a kamptozoan — is encountered with some regularity on Polysyncraton. We try to define the epibiotic situation of sessile marine organisms as composed of four epibiotic parameters: longevity or exposure time (A), epibiont load (E), colonizer pool (CP) and fouling-period (FP). Subsequently, these factors are combined to propose an “Antifouling Potential” index: AFP=(1−E/CP)×A/(FP+A). This index is intended to permit evaluating the relative antifouling defense potency to be expected in a given organism in a given epibiotic situation and to compare different cases of epibiosis and fouling

Protein synthesis studied in ras with methionine

Capítulo en: B.M. Mazoyer; W.D: Heiss; D. Comar (eds.). PET Studies on Amino Acid Metabolism and Protein Synthesis : Proceedings of a Workshop held in Lyon, France, within the framework of the European Community Medical and Public Health Research. Dordrecht: Springer, 1993, p.53-68. (Developments in Nuclear Medicine ; 23). ISBN 978-94-010-4706-7. ISBN 978-94-011-1620-6. DOI 10.1007/978-94-011-1620-6_41) Total brain radioactivity was found to be regionally correlated (r = 0.97) with radioactivity incorporated into proteins following a bolus injection of [14C-methyl]methionine. This suggests that regional differences in total label accumulation correspond to differences in the incorporation of label into proteins. 2) Under steady-state conditions (i.e., during continuous infusion of [14C-methyl]methionine), regional brain specific activity (SA) was found to be lower than the plasma SA. Brain SA was diluted by an endogenous source of free methionine likely to be from protein breakdown. Assuming that all endogenous brain methionine can contribute to protein synthesis, measuring labelled methionine incorporation (without accounting for tissue SA), would lead to underestimated rates. 3) In contrast to these results, similar studies carried out on the rat heart have shown a ratio of heart to plasma SA equivalent to unity. According to this, methionine recycling did not became apparent in the heart during the experimental time and under our experimental conditions.Peer Reviewe

Resting-state auditory network in tinnitus: a fMRI study

BACKGROUND AND PURPOSE: Positron emission tomography (PET) has the potential to improve our understanding of the preclinical pharmacokinetics and metabolism of therapeutic agents, and is easily translated to clinical studies in humans. However, studies involving proteins radiolabelled with clinically relevant PET isotopes are currently limited. Here we illustrate the potential of PET imaging in a preclinical study of the biodistribution and metabolism of (18)F-labelled IL-1 receptor antagonist ([(18)F]IL-1RA) using a novel [(18)F]-radiolabelling technique. EXPERIMENTAL APPROACH: IL-1RA was radiolabelled by reductive amination on lysine moieties with [(18)F]fluoroacetaldehyde. Sprague-Dawley rats were injected intravenously with [(18)F]IL-1RA and imaged with a PET camera for 2 h. For the study of IL-1RA metabolites by ex vivoγ-counting of samples, rats were killed 20 min, 1 h or 2 h after injection of [(18)F]IL-1RA. KEY RESULTS: [(18)F]IL-1RA distribution into the major organs of interest was as follows: kidneys >> liver > lungs >> brain. In lungs and liver, [(18)F]IL-1RA uptake peaked within 1 min post-injection then decreased rapidly to reach a plateau from 10 min post-injection. In the brain, the uptake exhibited slower pharmacokinetics with a smaller post-injection peak and a plateau from 6 min onward. IL-1RA was rapidly metabolized and these metabolites represented ∼40% of total activity in plasma and ∼80% in urine, 20 min after injection. CONCLUSIONS AND IMPLICATIONS: Preclinical PET imaging is a feasible method of assessing the biodistribution of new biological compounds of therapeutic interest rapidly. The biodistribution of [(18)F]IL-1RA reported here is in agreement with an earlier study suggesting low uptake in the normal brain, with rapid metabolism and excretion via the kidneys