Cerebral Pharmacodynamic Effects of 5-HT1B Receptor Stimulation

The purpose of this study is to show that PET-MR imaging can be used for obtaining a pharmacodynamic profile of drugs. By using the 5-HT1B receptor as target we also aim to find effect areas and sizes of the 5-HT1B receptor agonist sumatriptan.

Study Overview

• Status: Terminated
• Conditions: Healthy Volunteers
• Intervention / Treatment: Drug: Sumatriptan

Detailed Description

Recent technological advances in multimodal imaging have enabled the simultaneous acquisition of magnetic resonance imaging (MRI) and PET data. Whereas functional MRI (fMRI) provides excellent spatio-temporal resolution for localizing changes in brain activity, PET offers high sensitivity and neurochemical specificity. Together, PET and MRI measures have the potential to help clarify the neurochemical basis of changes in fMRI signal induced by selective exogenous ligands or endogenous neurotransmitter.

In the present study we will target the 5-HT1B receptor for which a selective radioligand exist (11C-AZ10419369). The receptor can be stimulated with the agonist sumatriptan, which is used for alleviating migraine attacks. The mechanism of action of sumatriptan is not precisely known and it is unknown to what degree sumatriptan crosses the blood-brain barrier and exerts its effect in the parenchyma. In this study we can determine the blood brain barrier penetration of sumatriptan and thereby evaluate Effect sizes, distribution of signal changes, and correlation between the occupancy at the 5-HT1B receptor in the parenchyma (measured by changes in BPND) and the hemodynamic response (measured by changes in CBF).

Ahead of the main study a pilot study will be conducted in which increasing doses of sumatriptan will be tested in the same subject to obtain a dose-response curve. At the same time side effects will be observed and scored. This serves to find the dose with maximum effect size but minimal side effects, which can then be used in the main study for all subjects.

• Study Type: Interventional
• Enrollment (Actual): 17
• Phase: Phase 1

Contacts and Locations

Study Locations

• Denmark
  • Copenhagen, Denmark, 2100
    • Neurobiology Research Unit, Rigshospitalet

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Healthy subjects
• Age 18-60

Exclusion Criteria:

• Primary psychiatric disease (DSM IV Axis I or WHO ICD-10 diagnostic classification).
• Present or former neurological diseases,
• Severe somatic disease
• Medication that can interfere with the test results.
• Doesn't speak Danish fluently or is severely, visually or hearing impaired.
• Information regarding former learning disabilities.
• Pregnancy at the time of the scanning
• Breast feeding
• MR-scanner incompatibility (metal in soft tissue)
• Alcohol or drug abuse
• Allergy to ingredients in used drugs
• Participation in experiments with radioactivity (>10 mSv) within the last year or considerable work-related exposure to radioactivity.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Sumatriptan; In the pilot study (an MR-only study) subjects will receive up to five doses of sumatriptan in the range of 10 ug/kg to 80 ug/kg. This allows us to establish a dose-response curve for each subject. Administration of sumatriptan in the pilot study will be spaced with approximately one week apart to avoid carry-over effects of the drug. In the main study (a PET-MR study), the sumatriptan dose with the maximal effect size and minimum side effects will be used for all subjects.

Drug: Sumatriptan; Sumatriptan is a 5-HT1B receptor agonist used for treatment of migraine attacks; Other Names: Imigran

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in 5-HT1B receptor binding as measured with [11C]AZ10419369	Both measures of receptor binding will be calculated from the same PET-MR acquisition.	Two binding potentials are obtained from the 120 min scan: Baseline BPND is determined from 0-50 min. Intervention BPND is determined from 50-120 min.
Changes in cerebral blood flow measured with pseudo continuous Arterial Spin Labeling	CBF will be measured continuous and within the acquisition a dynamic change in CBF upon administration of sumatriptan will be obtained.	CBF is measured 15 min prior and 30 min after the injection of sumatriptan giving 45 min of total CBF measurement time.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in [11C]AZ10419369 concentration in blood and plasma	Blood samples will be drawn throughout the acquisition time and radioactivity in blood and plasma will be measured.	At 2.5, 20, 49, 51, 90 and 120 min after injection of [11C]AZ10419369
Plasma concentration of sumatriptan	Blood samples will taken to measure the plasma concentration of the drug.	At -1, 1, 10, 20, 35 and 75 min after injection of sumatriptan

Collaborators and Investigators

• Sponsor: Gitte Moos Knudsen
• Investigators: Study Chair: Gitte M Knudsen, MD, DMSc, Neurobiology Research Unit, Rigshospitalet

Study record dates

Study Major Dates

• Study Start: September 1, 2016
• Primary Completion (Actual): June 1, 2019
• Study Completion (Actual): June 1, 2019

Study Registration Dates

• First Submitted: October 7, 2016
• First Submitted That Met QC Criteria: October 12, 2016
• First Posted (Estimate): October 13, 2016

Study Record Updates

• Last Update Posted (Actual): June 27, 2019
• Last Update Submitted That Met QC Criteria: June 25, 2019
• Last Verified: June 1, 2019

More Information

Terms related to this study

• Keywords: Sumatriptan; PET-MR; 5-HT1B receptor; phMRI; [11C]AZ10419369
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Serotonin Agents; Serotonin 5-HT1 Receptor Agonists; Serotonin Receptor Agonists; Vasoconstrictor Agents; Sumatriptan
• Other Study ID Numbers: NP3

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Via database of Center for Integrated Molecular Brain Imaging (Knudsen et al 2016, NeuroImage) data will be available for neuroscience research community contingent on approval by scientific board.