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Institute of Neuroscience and Medicine

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Clinical research:

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.

Darstellung eines dreidimensional rekonstruierten PET-Datensatzes

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.

Verdrängung des Radioliganden [18F]CPFPX durch unterschiedliche Dosen der gleichen, jedoch „kalten“ (d. h. nicht radioaktiven) Testsubstanz CPFPX

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.

Klinisches Beispiel für die Blockade eines Rezeptorsystems infolge einer längerfristigen Medikamenteneinnahme.

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:

Changes of A1 adenosine receptors (A1AR) in Huntington’s disease

Huntington’s disease (HD) is a neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the HD gene of autosomal dominant inheritance penetrating typically around the age of 40. Typical symptoms are choreatic movements and behavioural symptoms. Life expectancy is reduced in HD patients. In cooperation with the Huntington Centre at St. Josef University Hospital Bochum we studied changes of the A1AR at 8 manifest and 15 pre-manifest HD gene carriers versus 36 controls. Using PET and the radioligand [18F]CPFPX (developed in house by the Institute of Radiochemistry) we observed a global upregulation of the A1AR in early pemanifest gene carriers while A1AR availability decreased considerably in manifest patients (especially in the striatum). The amygdale was identified as the structure which showed the earliest changes.

A1-Adenosinrezeptoren bei Patienten mit Chorea Huntington im Vergleich zu Kontrollen

Fig. 4: Statistical parametric mapping of [18F]CPFPX binding potential (BPND) in 8 patients with manifest Huntington’s disease vs. 21 healthy age normalized controls. Pixel wise T-values are colour-coded (blue-green symbolizes a decrease and red-yellow an increase compared to controls).

Down-regulation of 5-HT2A receptors in the prodromal phase of schizophrenia

The empiric efficiency of serotonergic drugs in the psychotic type of mental disease suggested to image serotonergic receptors (here the 5-HT2A subtype) for the early detection of serotoninergic changes in schizophrenie. A sample of 14 subjects in at-risk mental states was recruited at the Department of Psychiatry of the University in Bonn. All subjects were strictly drug naïve. We detected decreased binding of the 5-HT2A radioligand [18F]altanserin by 15% in the right posterior insula and by 35% in the left amygdala (compared to 21 age matched healthy controls). The findings were highly significant at the group level and confirmed current pathobiochemical concepts of schizophrenia.      

Parametische PET-Darstellung der Gehirne von gesunden Kontrollpersonen (obere Zeile) sowie Personen in frühen (Mitte) und späten Prodromalstadien (untere Zeile).

Fig. 5: Parametric images of [18F]altanserin binding potential (BPP) corrected for partial volume effects in controls (top) and persons at early (middle) and late (bottom) prodromal state of schizophrenia. Note the decrease of [18F]altanserin binding in the striatum and posterior insula.

Up-regulation of 5-HT2A receptors in progressive supranuclear palsy (PSP)

PSP is characterised by aberrant phosphorylation of protein tau and neurodegeneration in midbrain structures. The clinical symptoms comprise atypical Parkinson symptoms with paresis of vertical eye movements and subcortical dementia. Currently, no efficient treatment is available. In a sample of 8 PSP patients recruited at the Department of Neurology of the university of Marburg we found an increase of 5-HT2A receptor density by 60% in the striatum reaching 138% in the right caudate nucleus (compared to 13 healthy age matched controls). In the substantia nigra 5-HT2A receptors were detectable in PSP but not control subjects. These brain regions are crucial for the initiation and control of movement programs.

Ausmaß der Atrophiein verschiedenen Hirnregionen bei Patienten mit PSP

Fig. 6: Study of 8 subjects with PSP versus 13 controls (CTRL). (A) T-maps resulting from a comparison of gray matter segments in PSP patients and controls using statistical parametric mapping (SPM) highlight cortical atrophy in PSP. (B) Averaged partial volume-corrected parametric maps displaying 5-HT2A binding potential BPP. (C) SPM T-maps display individual voxels with significantly decreased and increased BPP, respectively, thresholded at P = 0.001. (D) Comparison of averaged BPP maps of the nigro-striatal region in coronal sections (upper panel) and of the midbrain in axial sections (lower panel). Note increased specific binding bilaterally in the substantia nigra and striatum in PSP-patients. (E) Scatter plot demonstrating the correlation of the PSP rating score and the 5-HT2A binding potential BPP in the substantia nigra. The horizontal bar shows the average of controls.