I2PETPG - Imidazoline2 Binding Sites in a Group of Participants Diagnosed With AD

NCT02874820 | Terminated Early Phase 1

• 2 other identifiers: 16HH3243MR/L01307X/1
• Study Type: interventional
• Target: 2
• 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. 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

Alzheimer Disease

Keywords

Imidazoline Receptor 2; (4,5-dihydro-1H-imidazol-2-yl)-1-methyl-1H-indole; BU99008; [11C]-BU99008; Radionuclide Imaging; Molecular Imaging

Outcome Measures

Primary Outcomes (1)

• Density and distribution of Imidazoline 2 binding sites using either Total Volume of Distribution (VT) or Binding Potential (BP)

  The primary outcome of this study will be the determination of the regional density and distribution of the I2BS in human brain of participants with a diagnosis of early AD. The output parameter used to determine this will be derived from the most appropriate PET pharmacokinetic model for this ligand in human. However, from our current study of this ligand in healthy volunteers this will probably be the Volume of distribution (Vt) derived from the 2 tissue compartment model (2TCM).

  1 year

Study Arms (1)

Patient Group

EXPERIMENTAL

Baseline PET scan followed by a blocked PET scan

Radiation: [11C]BU99008; Drug: Idazoxan

Interventions

[11C]BU99008 RADIATION

Baseline and blocked scans

Patient Group

Idazoxan DRUG

Idazoxan dose up to 80mg

Patient Group

Eligibility Criteria

• Age: 50 Years - 80 Years
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male aged 50 to 80 years
• Subjects who meet the NIA-AA core clinical criteria for probable Alzheimer's disease dementia
• Clinical Dementia Rating (CDR) score of 0.5 or more and MMSE ≥ 17
• Subjects on acetylcholinesterase inhibitor or memantine therapy for Alzheimer's disease must be on a stable dose prior to baseline
• Subjects must have partners/caregivers able to accompany them during the study visits, as well as monitor for, and report, any adverse events to the study team in the week after scanning
• Non-smoker
• Willing to comply with protocol and lifestyle restrictions
• Excellent understanding of English (for questionnaires)
• Participant is ambulant and capable of attending a PET scan visit as an outpatient.
• Participants with female partners of child-bearing potential must agree to use one of the contraception methods listed in Section 7.5.1. 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.

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

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

Study Officials

• David J Nutt, MD

  Director of Centre for Neuropsychopharmacology, Imperial College London

  PRINCIPAL INVESTIGATOR

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: August 17, 2016
• First Posted: August 22, 2016
• Study Start: July 1, 2016
• Primary Completion: March 1, 2017
• Study Completion: July 1, 2017
• Last Updated: August 27, 2020

Record last verified: 2020-08

Locations

GB (1)