University of Michigan Hospitals

Funding for Human Subjects Research:

DOE: Office of Biological and Environmental Research (OBER)

$10,000.00 (Est.) for: Fiscal Year 2006
Five subjects were studied at a cost of $2,000 each.
Percent of funding associated with the use of human subjects: 1-20

Information on Use of Human Subjects:

This project involves the use of multiple protocols/subprojects.
Number of protocols/subprojects associated with this project: 3

Institutional Review Board (IRB) Review:
Type of Review: Full Board
Approving Institution: University of Michigan Hospitals
Most recent approval: 08/31/06
IRB approval number: 2002-0891

Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 0
Reporting period for number of human subjects: Fiscal Year 2006

Type(s) of Human Subjects Involvement:

External use of ionizing radiation on human subjects:

• For clinical research

Internal administration of radioactive substances to human subjects:

• For clinical research

(a. Objectives, b. Methodology, c. Ionizing Radiation, Radioactive Substances, or Chemical Substances to which human subjects are exposed, d. Involvement of Human Subjects [d.1. procedures used, d.2. risks if any])

OBJECTIVES AND METHODOLOGY

The general goal is to estimate multiple neuropharmacological parameters within a single non-invasive positron emission tomography (PET) procedure. In this new work, we seek to develop a method that involves injection of two different PET radiotracers, separated by 20 to 30 minutes, in a single dynamic acquisition but does not require arterial blood sampling. Such studies will offer many advantages for human PET imaging where the invasive, complicated, and time-consuming effort of arterial plasma sampling and metabolite correction are not always feasible. The research will develop, test, and validate data acquisition and analysis methods designed specifically for the purpose of quantifying multiple pharmacological measures non-invasively from dual-radioligand dynamic PET studies. These methods will use modified reference region techniques instead of input functions obtained from arterial blood sampling. We will apply a combination of Logan plot, reference tissue model, and shape analysis approaches for the estimation of multiple neuropharmacological parameters.

The significance of this research centers on the concept that, rather than examining particular aspects of the working brain in isolation, we would like to provide a broader more global view of cerebral function. We wish to be able to examine interactions between various neuropharmacological systems and to study effects that one neurotransmitter/receptor system has on another, not just to examine one component at a time without seeing how it fits into the overall workings of the human brain. Our previous work along the same line has shown it possible to measure multiple neuropharmacological parameters from a dual-radiotracer, single-acquisition PET study, but using a protocol that requires determination of the arterial plasma input functions for both radiotracers. This aspect of the experimental protocol is somewhat invasive requiring placement of an arterial catheter, and also is both labor intensive and time consuming since metabolite corrected concentration time courses are needed for both tracers. Many protocols for single-injection PET studies have been developed that avoid the need for input function determination. In this project, we seek to develop a method that involves injection of two different PET radiotracers (separated by a short time) in a single dynamic acquisition that does not require arterial blood sampling.

IONIZING RADIATION AND RADIOACTIVE SUBSTANCES

Subjects will have two 5 to 10 minute transmission scans performed for measurement of attenuation factors for the PET scan. Subjects involved in this project will be injected via venous catheter with one of the two following injection scenarios:
1) one injection of 12 mCi [11C]MP + two injections, 12 mCi each of [11C]RAC
OR
2) one injection of 12 mCi [11C]RAC + two injections, 12 mCi each of [11C]MP.

All injections will be administered via the intravenous catheter. Injections will be made as a discreet bolus and/or as a continuous infusion over the study duration.

INVOLVEMENT OF HUMAN SUBJECTS

A brief medical and neurologic screening will take less than one hour to complete. PET imaging will take approximately four hours to complete. A vein will be catheterized for injections. Subjects will be positioned in the PET scanner. A transmission scan will be done to calculate attenuation correction factors. Subjects will be injected with [11C]RAC. PET imaging will begin simultaneously. Twenty or thirty minutes later subjects will be injected with [11C]MP. Imaging will continue for another 60 minutes. The order of tracer injection will be switched. The first tracer will be injected as a bolus plus a continuous infusion. The second tracer will be injected as a bolus or fractionated into a bolus and continuous infusion.

Visual stimulation challenge studies will be performed to test identifiability of transport parameters from binding parameters. During one tracer administration, the subject will be scanned with eyes closed. When the other tracer is administered, the subject will be scanned while watching an alternating annual checkerboard throughout the first 15 minutes after the tracer administration is begun. This procedure selectively increases cerebral blood flow to the visual cortex, and hence the value of the transport rate constant in the visual cortex for one of the ligands should be increased, while not affecting the transport estimate for the other ligand or either of the binding parameters.

RISKS

Risks consist of low-level radiation exposure, cannulation of a cutaneous vein, and idiosyncratic/allergic reaction to the study radiopharmaceutical.

PRIVACY/CONFIDENTIALITY/CONSENT

A research subject will not be personally identified during presentation or write-up of the data. PET research data have limited accessibility. Written informed consent will be obtained during a face-to-face visit.

Institutional Review Board (IRB) Review:
Type of Review: Full Board
Approving Institution: University of Michigan Hospitals
Most recent approval: 08/24/06
IRB approval number: 2002-0893

Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 5
Reporting period for number of human subjects: Fiscal Year 2006

Type(s) of Human Subjects Involvement:

External use of ionizing radiation on human subjects:

• For clinical research

Internal administration of radioactive substances to human subjects:

• For clinical research

Collection of personally identifiable bodily materials (blood or blood products, urine, cells, tissue, teeth, organs, excreta, etc):

• Using bodily materials collected specifically for this project.

(a. Objectives, b. Methodology, c. Ionizing Radiation, Radioactive Substances, or Chemical Substances to which human subjects are exposed, d. Involvement of Human Subjects [d.1. procedures used, d.2. risks if any])

OBJECTIVES AND METHODOLOGY

The general goal is to estimate multiple neuropharmacological parameters within a single non-invasive positron emission tomography (PET) procedure. In this new work, we seek to develop a method that involves injection of two different PET radiotracers, separated by 20 to 30 minutes, in a single dynamic acquisition but does not require arterial blood sampling. Such studies will offer many advantages for human PET imaging where the invasive, complicated, and time-consuming effort of arterial plasma sampling and metabolite correction are not always feasible. The research will develop, test, and validate data acquisition and analysis methods designed specifically for the purpose of quantifying multiple pharmacological measures non-invasively from dual-radioligand dynamic PET studies. These methods will use modified reference region techniques instead of input functions obtained from arterial blood sampling. We will apply a combination of Logan plot, reference tissue model, and shape analysis approaches for the estimation of multiple neuropharmacological parameters.

The significance of this research centers on the concept that rather than examining particular aspects of the working brain in isolation, we would like to provide a broader, global view of cerebral function. We wish to be able to examine interactions between various neuropharmacological systems and to study effects that one neurotransmitter/receptor system has on another, not just to examine one component at a time without seeing how it fits into the overall workings of the human brain. Our previous work along the same line has shown it possible to measure multiple neuropharmacological parameters from a dual-radiotracer, single-acquisition PET study, but using a protocol that requires determination of the arterial plasma input functions for both radiotracers. This aspect of the experimental protocol is somewhat invasive requiring placement of an arterial catheter and also is both labor intensive and time consuming since metabolite corrected concentration time courses are needed for both tracers. Many protocols for single-injection PET studies have been developed that avoid the need for input function determination. In this project we seek to develop a method that involves injection of two different PET radiotracers (separated by a short time) in a single dynamic acquisition that does not require arterial blood sampling.

IONIZING RADIATION AND RADIOACTIVE SUBSTANCES

Subjects will have two 5 to 10 minute transmission scans performed for measurement of attenuation factors for the PET scan. Subjects involved in this research project will be injected via venous catheter with [11C]FMZ and [11C]PMP or [11C]BMP. The injection of these radiotracers allows for PET imaging of benzodiazepine receptor binding ([11C]FMZ) and cholinesterase activity ([11C]PMP and BMP).

INVOLVEMENT OF SUBJECTS

A brief medical and neurologic screening will take less than one hour to complete. PET imaging will take approximately four hours if completed in one day or 2.5 hours on each of two days.

Part One: A radial artery may be catheterized to allow for blood sampling. A vein will be catheterized for injections. Subjects will be positioned in the PET scanner. A transmission scan will be done to calculate attenuation correction factors. A pharmacologic intervention may be administered. This will be the intravenous administration of cold flumazenil. It will be injected as a bolus followed by continuous infusion for the duration of the study. Subjects will be injected with [11C]FMZ. Arterial blood sampling and dynamic PET imaging will begin simultaneously. Twenty or thirty minutes post-injection, subjects will be injected with [11C]PMP or [11C]BMP. Imaging and blood sampling will continue for sixty minutes. The order of tracer injection may be switched. The first tracer will be injected as a continuous infusion. The second tracer will be injected as a bolus or fractionated into a bolus and continuous infusion. An arterial input function will be generated and coupled with the PET images to generate quantitative images.

Part Two: An intravenous line is needed for the injection of [11C]FMZ and [11C]PMP. This line may also be used for the administration of cold flumazenil. A transmission scan will be performed. PET imaging will take 80 to 90 minutes to complete. No blood sampling will occur.

RISKS

Risks include low-level radiation exposure, cannulation of the radial artery, cannulation of a cutaneous vein, idiosyncratic/allergic reaction to the study radiopharmaceutical, and idiosyncratic/allergic reaction to pharmacologic intervention.

PRIVACY/CONFIDENTIALITY/CONSENT

A research subject will not be personally identified during presentation or report of the data. PET research data have limited accessibility. Written informed consent will be obtained during a face-to-face visit after the study has been fully explained to the research subject and all questions have been fully answered.

Institutional Review Board (IRB) Review:
Type of Review: Full Board
Approving Institution: University of Michigan Hospitals
Most recent approval: 08/24/06
IRB approval number: 2002-0894

Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 0
Reporting period for number of human subjects: Fiscal Year 2006

Type(s) of Human Subjects Involvement:

External use of ionizing radiation on human subjects:

• For clinical research

Internal administration of radioactive substances to human subjects:

• For clinical research

Collection of personally identifiable bodily materials (blood or blood products, urine, cells, tissue, teeth, organs, excreta, etc):

• Using bodily materials collected specifically for this project.

(a. Objectives, b. Methodology, c. Ionizing Radiation, Radioactive Substances, or Chemical Substances to which human subjects are exposed, d. Involvement of Human Subjects [d.1. procedures used, d.2. risks if any])

OBJECTIVES AND METHODOLOGY

The general goal is to estimate multiple neuropharmacological parameters within a single non-invasive positron emission tomography (PET) procedure. In this new work, we seek to develop a method that involves injection of two different PET radiotracers, separated by 20 to 30 minutes, in a single dynamic acquisition but does not require arterial blood sampling. Such studies will offer many advantages for human PET imaging where the invasive, complicated, and time-consuming effort of arterial plasma sampling and metabolite correction are not always feasible. The research will develop, test, and validate data acquisition and analysis methods designed specifically for the purpose of quantifying multiple pharmacological measures non-invasively from dual-radioligand dynamic PET studies. These methods will use modified reference region techniques instead of input functions obtained from arterial blood sampling. We will apply a combination of Logan plot, reference tissue model, and shape analysis approaches for the estimation of multiple neuropharmacological parameters.

The significance of this research centers on the concept that rather than examining particular aspects of the working brain in isolation, we would like to provide a broader more global view of cerebral function. We wish to be able to examine interactions between various neuropharmacological systems and to study effects that one neurotransmitter/receptor system has on another, not just to examine one component at a time without seeing how it fits into the overall workings of the human brain. Our previous work along the same line has shown it possible to measure multiple neuropharmacological parameters from a dual-radiotracer, single-acquisition PET study, but using a protocol that requires determination of the arterial plasma input functions for both radiotracers. This aspect of the experimental protocol is somewhat invasive requiring placement of an arterial catheter and also is both labor intensive and time consuming since metabolite corrected concentration time courses are needed for both tracers. Many protocols for single-injection PET studies have been developed that avoid the need for input function determination. In this project, we seek to develop a method that involves injection of two different PET radiotracers (separated by a short time) in a single dynamic acquisition that does not require arterial blood sampling.

IONIZING RADIATION AND RADIOACTIVE SUBSTANCES

Subjects will have two 5 to 10 minute transmission scans performed for measurement of attenuation factors for the PET scan. Subjects involved in this research project will be injected via venous catheter with [11C]FMZ and [11C]DTBZ. The injection of these radiotracers allows for PET imaging of benzodiazepine receptor binding ([11C]FMZ) and monoamine storage vesicles ([11C]DTBZ).

INVOLVEMENT OF SUBJECTS

Subjects will undergo a medical examination and physical history to rule out underlying abnormalities. Subjects will participate in a two-part PET imaging session of the brain. Subjects may be studied on one or two days, one day to one month apart.

Part One: A radial artery may be catheterized to allow for blood sampling. A vein will be catheterized for injections. Subjects will be positioned in the PET scanner. A transmission scan will be done to calculate attenuation correction factors. A pharmacologic intervention may be administered. This will be the intravenous administration of cold flumazenil. It will be injected as a bolus followed by continuous infusion for the duration of the study. Subjects will be injected with [11C]FMZ. Arterial blood sampling and dynamic PET imaging will begin simultaneously. Twenty or thirty minutes post-injection, subjects will be injected with [11C]DTBZ. Imaging and blood sampling will continue for sixty minutes. The order of tracer injection may be switched. The first tracer will be injected as a continuous infusion. The second tracer will be injected as a bolus or fractionated into a bolus and continuous infusion. An arterial input function will be generated and coupled with the PET images to generate quantitative images.

Part Two: An intravenous line is needed for the injection of [11C]FMZ and/or [11C]DTBZ. This line may also be used for the administration of cold flumazenil. A transmission scan will be performed. PET imaging will take 80 to 90 minutes to complete. No blood sampling will occur.

RISKS

Risks consist of low-level radiation exposure, cannulation of the radial artery, cannulation of a cutaneous vein, idiosyncratic/allergic reaction to the study radiopharmaceutical, and idiosyncratic/allergic reaction to pharmacologic intervention.

PRIVACY/CONFIDENTIALITY/CONSENT

A research subject will not be personally identified during presentation or report of the data. PET research data have limited accessibility. Written informed consent will be obtained during a face-to-face visit after the study has been fully explained to the research subject and all questions have been fully answered.