Projects in basic research:
In general, the scope of clinical studies in humans ranges from new diagnostic and treatment concepts to the identification of “drugable” candidates. They comprise the investigation of pharmacological actions and side effects. Clinical drug development is divided into four phases. Phase I investigates safety, tolerability, pharmacokinetics and dose finding in healthy volunteers. Phase II is dedicated to a proof of concept and the assessment of dose response relationships in ill subjects. Phase IIa comprises early pilot studies in small populations intended to identify the suitable patients and dosing schedules. Phase IIb involves the treatment of larger sets of patients under more specified criteria. During Phase III the drug is tested in large cohorts of patients with rigorous end points indented to generate robust statistical data on efficiency and non-inferiority to established treatments. After each phase a large number of candidates has to be excluded and only those which successfully passed Phase III are eligible to market authorization. Phase IV is related to post marketing investigations including monitoring for rare and delayed side effects.
Our contributions to clinical studies are related to the use of positron emission tomography (PET) focussed at neurological and psychiatric diseases. Our primary interest is to find early and specific biomarkers suitable for neuro-imaging. PET offers a unique and quick possibility for dose finding in healthy volunteers via occupation / displacement studies. Further, it allows to monitor the availability of a target structure longitudinally during the course of treatment. This approach is of special benefit in the neuro-psychiatric domain as clinical effects are often delayed and of high inter-individual variability.
Besides clinical studies, we apply neuro-receptor PET also as an instrument for molecular brain research which allows accessing basic and pathophysiological and pathobiochemical processes minimal-invasively and longitudinally.
Dose finding studies
Usually dosing of a drug is considered sufficient if more than 50% of target structures – e.g. receptors - are occupied. The degree of occupation can be measured with a suitable radioligand either by occupation or displacement studies. Occupation studies consist of two PET measurements with and without the application of the test compound (c.f. Fig. 3). Displacement experiments (c.f. Fig. 1 and Fig. 2) start with establishing distribution equilibrium of a radioligand by a bolus/infusion application schedule. After measuring the radioligand binding at baseline a test dose is applied and under continued radioligand application. The difference between the two states allows estimating the competitive efficacy of the radioligand.
Fig. 1: Radioligand displacement study. A distribution equilibrium of the 5-HT2A radioligand [18F]altanserin is established. (A) shows the cerebral distribution given as binding potential DV3’ (=BPP) at baseline, averaged across 50-90 min after start of the bolus/infusion application. At 90 min, 10 mg ketanserin, a 5-HT2A anti-hypertonic, were infused over 5 min followed by 6 mg/h maintenance dose. (B) shows DV3’ after installation of a new equilibrium averaged across 140-180 min. 87% of specific radioligand binding were displaced. It can be concluded that 18.5 mg of ketanserin lead to 87% receptor occupation. Given is a 3D surface rendering of an individual brain. The maximum DV3’ within a depth range of 6 mm from the coregistered PET dataset was projected at the surface.
Fig. 2: Displacement of the radioligand [18F]CPFPX by different doses of the non-radioactive (“cold”) 19F isotopologue CPFPX. This type of experiment allows to estimate the in vivo dissociation constant KD and is a pivotal step in dose finding. Together with PK data, such as the biological plasma half-life, the amount and number of daily doses of a candidate drug can be estimated.
Fig. 3: Example of an occupation study. The subject received a [18F]altanserin PET scan before and 36h after a treatment of 5 mg/d of the atypic neuroleptic olanzapin for 70 days. Note the full blockade of 5-HT2A receptors at this condition.
Clinical neuroscience – target identification and validation / early diagnostics
We apply molecular neuroimaging with PET to compare defined clinical and healthy cohorts in order to establish whether, when and how much neuroreceptors are changed in a given clinical condition. Particularly, diagnostic tools for early recognition are of interest as well as identifying targets for therapeutic interventions. In the neuropsychiatric domain many diseases are characterised by a presymptomatic or prodromal phase which precedes the symptomatic or clinically manifest phase. While clinical symptoms are still ambiguous distinct neurochemical changes can already provide early diagnostic indicators, which substantiate the indication for early therapeutic interventions.