I2PETHV - Quantification and Localisation of Imidazoline2 Binding Sites in Healthy Volunteers Using [11C]BU99008 a Positron Emission Tomography Study
试验速览
- 阶段
- 早期 1 期
- 状态
- 已完成
- 入组人数
- 20
- 试验地点
- 1
- 主要终点
- Determination of the Regional Density and Distribution of I2BS in Healthy Human Brain (1TCM Model)
研究概览
简要总结
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.
详细描述
This study will consist of three parts; Part A, B and C. Part A will involve up to 10 healthy subjects in order to determine the number and regional location of I2BS in healthy human brain following administration of [11C]BU99008. In Part B up to 6 healthy subjects will be recruited to provide sufficient PET data to quantify the intra- and inter-subject variability in the regional expression of I2BS in healthy human brain. Finally, in Part C up to 6 healthy subjects will be recruited in order to determine the distribution of I2BS in the whole body following administration of [11C]BU99008.
The three parts of this study will be conducted in series, and only if each part is successful will the investigators progress to the next. This will allow us to terminate the study early, and hence prevent the un-necessary exposure of participants to ionising radiation, if the emerging data shows a clear No-go decision to progress with this PET ligand.
Potential participants that pass the initial telephone screen will be invited to a screening visit where their eligibility to take part in the study will be determined and informed consent taken. This will be at the Imperial CRF and Imanova Ltd. The screening will consist of an interview where the study will be discussed and explained. The participants'understanding of the procedure, requirements and commitments confirmed and any questions answered before informed consent taken. In addition to this interview the participants personal details and demographics will be recorded and a psychiatric and medical history taken as well as the following:
- Semi-structured interviews/questionnaires will be completed: Mini International Neuropsychiatric Interview 5 (MINI 5), Cognitive diagnostic test for dementia (CAMCOG)
- A medical examination and blood taken for clinical laboratory testing.
- A structural MRI.
- Review of your medical history and current state of health, including questions about psychiatric symptoms and your use of prescription and non-prescription drugs, as well as your use of illegal drugs and alcohol.
- Physical examination such as measurements of blood pressure and heart rate, ECG.
- Collecting a urine sample to check for presence of drugs.
- Alcohol breath test.
- An "Allen's Test" will be performed to check the blood supply to your hand.
- Other questionnaires: Hospital Anxiety and Depression Scale (HADS), Eysenck personality (revised) (EPQ-R25), Spielberger Trait Anxiety Inventory (STAI), and MRI safety Participants that are eligible will then be invited to take part in the study, either Parts A, B or C as detailed below.
Below is the intended schedule of scanning for this study. However, if for some reason it is necessary to cancel or suspend a scan due to radioligand production failure, scanner failure, etc., the participant will be asked to return on another day to. This will only happen if they have not had the radioligand administered by the time the study is suspended. As detailed below cannulae will be introduced to collect blood for various analysis on the study days (approximately 120 mL). The blood collected for any one participant will not exceed 500 mL for the entire study.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Basic Science
- 盲法
- None
入排标准
- 年龄范围
- 40 Years 至 65 Years（Adult, Older Adult）
- 性别
- Male
- 接受健康志愿者
- 是
入选标准
- •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.
排除标准
- •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.
- •Previous inclusion in a research and/or medical protocol involving nuclear medicine, PET or radiological investigations or occupational exposure resulting in radiation exposure greater than 10 mSv over the past 3 years or greater than 10 mSv in a single year including the proposed study. Clinical exposure from which the subject receives a direct benefit is not included in these calculations.
- •Previous inclusion in a research and/or medical protocol involving study medication within the last 3 months
- •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.)
研究组 & 干预措施
Healthy Volunteers
干预措施: [11C]BU99008 (Radiation)
Healthy Volunteers
干预措施: Idazoxan (Drug)
Healthy Volunteers
干预措施: Isocarboxazid (Drug)
结局指标
主要结局
Determination of the Regional Density and Distribution of I2BS in Healthy Human Brain (1TCM Model)
时间窗: 1 week
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).
Determination of the Regional Density and Distribution of I2BS in Healthy Human Brain (2TCM Model)
时间窗: 1 week
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).
Determination of the Regional Density and Distribution of I2BS in Healthy Human Brain (MA Model)
时间窗: 1 week
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).
次要结局
- 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)