I2PETHV - Imidazoline2 Binding Site in Healthy Volunteers

NCT02323217 | Completed Early Phase 1 Results

• 2 other identifiers: 14HH2250MR/L01307X/1
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

Brief Summary

The imdazoline2 binding site (I2BS) is known to reside inside astrocytes. Changes in the numbers of I2BS in post mortem tissue has implicated them in a range of psychiatric conditions such as depression and addiction, along with neurodegenerative disorders such as Alzheimer's disease and Huntington's chorea. Preclinical studies have also demonstrated functional interactions with the opioid system, where I2BS ligands have been shown to affect tolerance to morphine and alleviate some of the morphine withdrawal syndrome in rats. Recently the I2BS and I2BS ligands have been shown to have some interesting analgesic effects in different models of pain and a novel I2BS ligand, CR4056, is currently undergoing Phase II clinical trials as a novel treatment for neuropathic pain and acute non- specific pain states. The location of I2BS on astrocytic glial cells and the possibility that they may in some way regulate glial fibrillary acidic protein have led to increased interest into the role of I2BS and I2BS ligands in conditions characterised by marked gliosis. The number of I2BS has been shown to increase in Alzheimer's disease post mortem, and it has also been suggested that I2BS may be a marker for the severity and malignancy of human glioblastomas. The lack of suitable imaging tools for the I2BS has meant that information regarding the number and distribution of I2BS in the brain has come from preclinical species and in vitro post-mortem studies. The recent development of \[11C\]BU99008 as a suitable PET ligand to quantify I2BS in vivo, enables the direct quantification of I2BS availability and regional distribution in the living human brain. In this study the investigators plan to utilise \[11C\]BU99008 to quantify the regional brain availability of I2BS in the human brain in vivo using PET.

Conditions

Healthy Volunteers; Alzheimer Disease; Molecular Imaging

Keywords

Imidazoline Receptor 2; (4,5-dihydro-1H-imidazol-2-yl)-1-methyl-1H-indole; BU99008; Radionuclide Imaging; Molecular Imaging; Healthy Volunteers; Alzheimer Disease

Outcome Measures

Primary Outcomes (3)

• Determination of the Regional Density and Distribution of I2BS in Healthy Human Brain (1TCM Model)

  The determination of the regional density and distribution of the I2BS in human brain of healthy volunteers. The output parameter used to determine this will be derived from the most appropriate PET pharmacokinetic model for this ligand in human e.g. Total Volume of Distribution (VT) or Binding Potential (BP). Regional time-activity data were generated from arterial plasma input functions corrected for metabolites using the most appropriate model to derive the outcome measure VT (regional distribution volume). All image processing and kinetic analyses were performed in MIAKAT. The Akaike model selection criteria were used to determine the most appropriate model to describe these data. The calculated criteria for the three main models are: one-tissue (1TCM) and two-tissue (2TCM) compartmental models, and multilinear analysis model (MA).

  1 week

• Determination of the Regional Density and Distribution of I2BS in Healthy Human Brain (2TCM Model)

  The determination of the regional density and distribution of the I2BS in human brain of healthy volunteers. The output parameter used to determine this will be derived from the most appropriate PET pharmacokinetic model for this ligand in human e.g. Total Volume of Distribution (VT) or Binding Potential (BP). Regional time-activity data were generated from arterial plasma input functions corrected for metabolites using the most appropriate model to derive the outcome measure VT (regional distribution volume). All image processing and kinetic analyses were performed in MIAKAT. The Akaike model selection criteria were used to determine the most appropriate model to describe these data. The calculated criteria for the three main models are: one-tissue (1TCM) and two-tissue (2TCM) compartmental models, and multilinear analysis model (MA).

  1 week

• Determination of the Regional Density and Distribution of I2BS in Healthy Human Brain (MA Model)

  The determination of the regional density and distribution of the I2BS in human brain of healthy volunteers. The output parameter used to determine this will be derived from the most appropriate PET pharmacokinetic model for this ligand in human e.g. Total Volume of Distribution (VT) or Binding Potential (BP). Regional time-activity data were generated from arterial plasma input functions corrected for metabolites using the most appropriate model to derive the outcome measure VT (regional distribution volume). All image processing and kinetic analyses were performed in MIAKAT. The Akaike model selection criteria were used to determine the most appropriate model to describe these data. The calculated criteria for the three main models are: one-tissue (1TCM) and two-tissue (2TCM) compartmental models, and multilinear analysis model (MA).

  1 week

Secondary Outcomes (2)

• Intra- and Inter-Subject Variability in Brain Expression of Imidazoline 2 Binding Sites, Measured Using Coefficient of Variability (%COV), Determined From Either Total Volume of Distribution (VT) or Binding Potential (BP).

  1 year

• Peripheral Distribution of Imidazoline 2 Binding Sites Using Either Total Volume of Distribution (VT) or Binding Potential (BP)

  1 year

Study Arms (1)

Healthy Volunteers

EXPERIMENTAL

Radiation: [11C]BU99008; Drug: Idazoxan; Drug: Isocarboxazid

Interventions

[11C]BU99008 RADIATION

Baseline Scan, Test-ReTest or Dosimetry

Healthy Volunteers

Idazoxan DRUG

Idazoxan block of \[11C\]BU99008

Healthy Volunteers

Isocarboxazid DRUG

Isocarboxazid block of \[11C\]BU99008

Healthy Volunteers

Eligibility Criteria

• Age: 40 Years - 65 Years
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male between 40 and 65 years at the time of signing the informed consent Non-smoker
• Willing to comply with protocol and lifestyle restrictions
• Excellent understanding of English (for questionnaires)
• Subject is ambulant and capable of attending a PET scan visit as an outpatient.
• Subjects with female partners of child-bearing potential must agree to use one of the contraception methods permitted by the study. This criterion must be followed from after the first PET Scan until after the follow-up contact.
• Adequate collateral flow to the radial and ulnar arteries in both hands as determined by an Allen's test.
• Body weight ≥50 kg.
• Healthy subjects are defined as individuals who are free from clinically significant illness or disease as determined by their medical history (including family), physical examination, objective physiological measures, previous laboratory studies, and other tests.
• Successful completion of the CAMCOG.

You may not qualify if:

• Current or past history of major psychiatric disorder
• Current or past history of substance use disorder
• Clinically significant brain injury or abnormality
• Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
• History of or suffers from claustrophobia or subject feels unable to lie flat and still on their back for a period of up to 2 hours in the PET/CT scanner.
• In the opinion of the study team they are unlikely to comply with the study protocol and restrictions that it imposes.
• Contraindications for subjects undergoing an MR scan (including but not limited to metal implants pacemakers, etc.)

Sponsors & Collaborators

• Imperial College London: lead
• GlaxoSmithKline: collaborator

Study Sites (1)

Centre for Neuropsychopharmacology; Division of Brain Sciences; Imperial College London; Burlington Danes Building; Hammersmith Hospital campus; 160 Du Cane Road

London, W12 0NN, United Kingdom

Location

MeSH Terms

Conditions

Alzheimer Disease

Interventions

Idazoxan; Isocarboxazid

Condition Hierarchy (Ancestors)

Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Dioxanes; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Isoxazoles

Results Point of Contact

• Title: Dr Robin J Tyacke
• Organization: Imperial College London

r.tyacke@imperial.ac.uk

(0)20 7594 7096

Study Officials

• David J Nutt, MD

  Director of Centre for Neuropsychopharmacology, Imperial College London

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: NA
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 11, 2014
• First Posted: December 23, 2014
• Study Start: January 1, 2015
• Primary Completion: February 1, 2016
• Study Completion: July 1, 2016
• Last Updated: November 15, 2021
• Results First Posted: November 15, 2021

Record last verified: 2021-10

Locations

GB (1)