Evaluation of a novel series of fluorine-18-labeled imidazobenzodiazepines as potential new positron emission tomography radioligands for the GABAA receptor.

INTRODUCTION: [(11)C]Flumazenil has been used to study the GABAA receptor in many preclinical and clinical studies, but the short half-life of carbon-11 means that this molecule is restricted to use by investigators with access to on-site cyclotron and radiosynthesis facilities. The radiosynthesis of [(18)F]flumazenil has been evaluated by several groups, but the radiochemical yield can be low and inconsistent. We previously reported a series of fluorine-18-labeled imidazobenzodiazepine-based ligands for the GABAA receptor, which had significantly improved radiosynthesis yields. Here we report the in vivo evaluation and comparison of the distribution, metabolism and specificity of the novel ligands in comparison with [(18)F]flumazenil. METHODS: In vivo biodistribution studies, at time points up to 90min post-injection, were performed in naïve rats to compare the performance of the novel compounds with particular attention paid to regional brain uptake and clearance. In vivo metabolism studies were carried out to determine the percentage of parent compound remaining in the plasma and brain at selected time points. Blocking studies were carried out, using pre-treatment of the test animals with either bretazenil or unlabeled fluorine-19 test compound, to determine the levels of specific and non-specific binding in selected brain regions. RESULTS: Two of the 12 new compounds were rejected due to poor biodistribution showing significant bone uptake. Some of the compounds showed insufficient whole brain uptake or limited evidence of differential binding to GABAA-rich brain regions to warrant further investigation. Four of the compounds were selected for in vivo metabolism and blocking studies. Overall, the studies indicated that two compounds 3 and 5 showed comparable or improved performance compared with [(18)F]flumazenil, with respect to distribution, metabolic profile and specific binding. CONCLUSIONS: These studies have demonstrated that compounds based on [(18)F]flumazenil, but with alterations to allow improved radiosynthesis, can be prepared which have ideal properties and warrant further evaluation as PET agents for the GABAA receptor. In particular, compounds 3 and 5 show very promising profiles with specific binding and in vivo stability comparable to flumazenil.

The development of potential new fluorine-18 labelled radiotracers for imaging the GABA(A) receptor.

Positron emission tomography (PET) using the tracer [(11)C]Flumazenil has shown changes in the distribution and expression of the GABA(A) receptor in a range of neurological conditions and injury states. We aim to develop a fluorine-18 labelled PET agent with comparable properties to [(11)C]Flumazenil. In this study we make a direct comparison between the currently known fluorine-18 labelled GABA(A) radiotracers and novel imidazobenzodiazepine ligands. A focussed library of novel compound was designed and synthesised where the fluorine containing moiety and the position of attachment is varied. The in vitro affinity of twenty-two compounds for the GABA(A) receptor was measured. Compounds containing a fluoroalkyl amide or a longer chain ester group were eliminated due to low potency. The fluorine-18 radiochemistry of one compound from each structural type was assessed to confirm that an automated radiosynthesis in good yield was feasible. Eleven of the novel compounds assessed appeared suitable for in vivo assessment as PET tracers.

Clinical outcomes of single-visit oral prophylaxis: a practice-based randomised controlled trial.

BACKGROUND: Practice-based general dental practitioners routinely provide "scale and polish" or "oral prophylaxis" to patients attending their practices. Despite its routine provision, there is no evidence to support the clinical effectiveness of single-visit scale and polish, nor the frequency at which it should be provided. A recent systematic review recommended that future trials investigating scale and polish should involve dental practice patients. METHODS: A practice-based parallel randomised controlled trial with 24-month follow-up was conducted. Healthy adults (Basic Periodontal Examination [BPE] codes <3) were randomly assigned to 3 groups (6-month, 12-month, or 24-month interval between scale and polish). The primary outcome was gingival bleeding with the hypothesis that 6-monthly scale and polish would result in lower prevalence than 12-month or 24-month frequency. Follow-up measurements were recorded by examiners blinded to the allocation. 125, 122 and 122 participants were randomised to the 6-month, 12-month and 24-month groups respectively. Complete data set analyses were conducted for 307 participants: 107, 100, and 100 in the 6-month, 12-month and 24-month groups respectively. Chi-square test and ANOVA were used to compare treatment groups at follow-up. Logistic regression and ANCOVA were used to estimate the relationship between outcome and treatment group, adjusted for baseline values. Multiple imputation analyses were also carried out for participants with incomplete data sets. RESULTS: Prevalence of gingival bleeding at follow-up was 78.5% (6-month), 78% (12-month) and 82% (24-month) (p = 0.746). There were no statistically significant differences between groups with respect to follow-up prevalence of plaque and calculus. Statistically significant differences detected in the amount (millimetres) of calculus were too small to be clinically significant. Seventeen (4.6%) participants were withdrawn from the trial to receive additional treatment. CONCLUSIONS: This trial could not identify any differences in outcomes for single-visit scale and polish provided at 6, 12 and 24 month frequencies for healthy patients (with no significant periodontal disease). However, this is the first trial of scale and polish which has been conducted in a general practice setting and the results are not conclusive. Larger trials with more comprehensive measurement and long-term follow up need to be undertaken to provide a firm evidence base for this intervention. This trial informs the design of future practice-based trials on this subject.