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Bolus infusion scheme for the adjustment of steady state [11C]Flumazenil levels in the grey matter for neuroreceptor imaging

7th August 2020

Jörg Mauler, Alexander Heinzel, Andreas Matusch, Hans Herzog, Irene Neuner, Jürgen Scheins, Christine Wyss, Jürgen Dammers, Markus Lang, Johannes Ermert, Bernd Neumaier, Karl-Josef Langen, N. Jon Shah

By combining positron emission tomography (PET) imaging with magnetic resonance imaging (MRI) of the brain, it is possible to investigate challenge-related changes in ligand binding to neuroreceptors, while simultaneously measuring neuroactivation or blood flow. Based on this information, researchers and physicians can determine and assess a range of neurological conditions, such as the binding of chemical messengers to GABA-receptors under visual-emotional stimulation in depressive patients and normal controls. At the same time, the level and location of the associated reduced/enhanced neurological activity can be observed.

For the PET part of the examination, the patient or subject is injected with a radiotracer, which is administered as a bolus, followed by a continuous infusion to maintain the initially achieved ligand concentration. Once the radiotracer has achieved a steady state, it is possible to observe alterations in ligand neuroreceptor binding through changes in distribution volumes. In order to minimise the radiation dose to the subject, while maximising the evaluable measuring time, it is imperative that this steady state of equilibrium be reached as quickly as possible. However, previous approaches to this have been complicated and required additional volunteers.

In this study, an iterative procedure for establishing an administration scheme to obtain steady-state [11C]flumazenil concentrations in grey matter in the human brain is presented. In order to achieve a steady state in the shortest possible time, the bolus infusion ratio from a previous examination was adapted to fit the subsequent examination. The study was based on a cohort of 17 male volunteers. Boli and infusions with different weightings were given to the subjects and were characterised by kbol values from 74 min down to 42 min. Metabolite analysis was used to ascertain the value of unmetabolised flumazenil in the plasma, and PET imaging was used to assess its binding in the grey matter. The flumazenil time-activity curves in the brain were decomposed into activity contributions from pure grey and white matter and analysed for 12 volumes of interest.

Although the curves highlighted a large variability in metabolic rates between the subjects, a kbol value of 54.3 min was found to be a reliable value to provide flumazenil equilibrium conditions in the majority of the volumes of interest and cases. Based on the findings of this study, it is anticipated that the method will be transferred to other ligand neuroreceptor systems, which will help to reduce the number of required volunteers in the underlying studies.

Original publication:

Bolus infusion scheme for the adjustment of steady state [11C]Flumazenil levels in the grey matter and in the blood plasma for neuroreceptor imaging