Electron spin resonance spectroscopy (ESR) of the nitroxide labelled fatty acid probes (5-, 16-doxyl stearic acid) was used to monitor the micelle microviscosity of three surfactants at various concentrations in aqueous solution: sodium dodecyl sulphate (SDS), dodecyltrimethylammonium bromide (DTAB) and cetyltrimethylammonium bromide (CTAB). At low surfactant concentration, there is no micelle, the ESR probe is dissolved in water/surfactant homogeneous phase and gives his microviscosity. At higher surfactant concentration, an abrupt increase in microviscosity indicates the apparition of micelles and, the solubilization of the probes in micelles. The microviscosity of the three surfactants, in a large surfactant range, was obtained as well as the critical micelle concentration (CMC). The microviscosity increased slightly with the increase in surfactant concentration. Phosphate buffer lowered the CMC value and generally increased the microviscosity.

Synaptic vesicle protein 2 isoforms are critical for proper nervous system function and are involved in vesicle trafficking. The synaptic vesicle protein 2A (SV2A) isoform has been identified as the binding site of the antiepileptic levetiracetam (LEV), making it an interesting therapeutic target for epilepsy. 18 F-UCB-H is a novel PET imaging agent with a nanomolar affinity for human SV2A. Methods: Preclinical PET studies were performed with isoflurane-anesthetized rats. The arterial input function was measured with an arteriovenous shunt and a β-microprobe system. 18 F-UCB-H was injected intravenously (bolus of 140 ± 20 MBq). Results: Brain uptake of 18 F-UCB-H was high, matching the expected homogeneous distribution of SV2A. The distribution volume (V t ) for 18 F-UCB-H was calculated with Logan graphic analysis, and the effect of LEV pretreatment on V t was measured. In control animals the whole-brain V t was 9.76 ± 0.52 mL/cm 3 (mean ± SD; n 5 4; test-retest), and the reproducibility in test-retest studies was 10.4% ± 6.5% (mean ± SD). The uptake of 18 F-UCB-H was dose dependently blocked by pretreatment with LEV (0.1-100 mg/kg intravenously). Conclusion: Our results indicated that 18 F-UCB-H is a suitable radiotracer for the imaging of SV2A in vivo. To our knowledge, this is the first PET tracer for the in vivo quantification of SV2A. The necessary steps for the implementation of 18 F-UCB-H production under good manufacturing practice conditions and the first human studies are being planned.

Purpose: Loss of brain synapses is an early pathological feature of Alzheimer's disease. The current study assessed synaptic loss in vivo with Positron Emission Tomography and an 18Flabelled radiotracer of the synaptic vesicle protein 2A, [18F]UCB-H. Methods: Twenty-four patients with Mild Cognitive Impairment or Alzheimer's disease and positive [18F]Flutemetamol amyloid-PET were compared to nineteen healthy controls. [18F]UCB-H brain uptake was quantified with Logan graphical analysis using an imagederived blood input function. SPM12 and regions-of-interest (ROI) analyses were used for group comparisons of regional brain distribution volumes and for correlation with cognitive measures. Results: A significant decrease of [18F]UCB-H uptake was observed in several cortical areas (11 to 18% difference) and in the thalamus (16% difference), with the largest effect size in the hippocampus (31% difference). Reduced hippocampal uptake was related to patients' cognitive decline (ROI analysis) and unawareness of memory problems (SPM and ROI analyses). Conclusions: The findings thus highlight predominant synaptic loss in the hippocampus, confirming previous autopsy-based studies and a recent PET study with an 11C-labelled SV2A radiotracer. [18F]UCB-H PET allows to image in vivo synaptic changes in Alzheimer's disease and to relate them to patients' cognitive impairment.

IntroductionBrain distribution of synaptic vesicle protein 2A was measured with fluorine-18 UCB-H ([18F]UCB-H) and positron emission tomography (PET).MethodsImages of synaptic density were acquired in healthy volunteers (two young participants and two seniors). Input function was measured by arterial blood sampling (arterial input function) and derived from PET images using carotid activity (image-derived input function). Logan graphical analysis was used to estimate regional synaptic vesicle protein 2A distribution volume.Results[18F]UCB-H uptake was ubiquitous in cortical and subcortical gray matter. Arterial input function and image-derived input function provided regional distribution volume with a high linear relationship.DiscussionThe cerebral distribution of [18F]UCB-H is similar to that recently observed with carbon-11 UCB-J ([11C]UCB-J). An accurate [18F]UCB-H quantification can be performed without invasive arterial blood sampling when no suitable reference region is available, using dynamic PET carotid activity. Brain synaptic density can be studied in vivo in normal and pathological aging.

This first human dosimetry study of [(18)F]UCB-H indicated that the tracer shows similar radiation burdens to widely used common clinical tracers. Single injections of at maximum 672 MBq for US practice and 649 MBq for European practice keep radiation exposure below recommended limits. Recently published preclinical dosimetry data extrapolated from mice provided satisfactory prediction of total body and effective dose but showed significant differences in organ absorbed doses compared to human data.