Dr. David E. Kuhl
Division of Nuclear Medicine
B1 G505 UH
Ann Arbor, MI 48109-0028
Phone: 734-936-5388
Fax: 734-936-8182
E-mail: dkuhl@umich.edu
Number of Human Subjects projects reported: 1
| UMH-87-DE-FG02-87ER60561 | "Advancing PET Science for New Measures of Brain Function" |
"Advancing PET Science for New Measures of Brain Function"
Principal Investigator: Dr. David E. Kuhl, University of Michigan Hospitals
Project started in: 1987
Funding for Human Subjects Research:
This project involves the use of multiple protocols/subprojects.
Number of protocols/subprojects associated with this project: 5
Institutional Review Board (IRB) Review:
Type of Review: Full Board
Approving Institution: University of Michigan Hospitals
Most recent approval: 09/04/02
IRB approval number: 1999-0683
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 6
Reporting period for number of human subjects:
Fiscal Year 2002
Type(s) of Human Subjects Involvement:
OBJECTIVES AND METHODOLOGY
The goal of this research is to develop and test methods to study multiple neuropharmacological parameters simultaneously using positron emission tomography (PET). Currently, we are completing the initial phase of this research proving the feasibility of performing dual tracer studies which reduce the time that currently is required for the subject to complete the scan. Results appear promising and demonstrate that multiple neuropharmacological measures can be made in a single scanning session. We have studied the two pairs of tracers with a dual-tracer protocol: 1) [11C]flumazenil (FMZ) and [11C]dihydrotetrabenazine (DTBZ), two ligands that bind reversibly; and 2) [11C]flumazenil (FMZ) and N-[11C]methylpiperidyl propionate (PMP), one reversible and one irreversible ligand. The goal of this current project is to extend this work with two tracers, both that bind irreversibly: N-[11C]methylpiperidyl butyrate (nBMP) and N-[11C]methylpiperidyl propionate (PMP). In the dual tracer approach, only a single "overlapping" PET study (instead of two full PET studies) is acquired and the duration of the entire study is shortened by 2 hours. Kinetic modeling and data analysis procedures have been developed and implemented, and applied to the preliminary studies in normal human subjects performed to prove practical feasibility of the method. In addition, these two tracers, which are irreversibly hydrolyzed at differing rates by two different cholinesterases, acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Human studies with this pair of radiotracers will permit the quantification of the regional activity of both AChE and BuChE by comparison of the hydrolysis rates of PMP and nBMP measured by PET study.
Brain functions are modulated by connections between cerebral structures and interactions among neurochemical systems. Disease processes often involve multiple cerebral structures and neurochemical systems that interact with each other. Changes in a neurochemical system in one part of the brain consequently affect other neurochemical systems in different areas of the brain. We would like to validate methods that can provide a broader more global view of cerebral function. We wish to examine interactions between various neuropharmacological systems and to study effects that one neurotransmitter/receptor system has on another. If one has to perform two PET studies to examine two distinct neuropharmacologic measures, several obvious limitations arise: 1) long study times make it difficult to study certain patients; 2) obtaining neuropharmacologic measures at two distinct points in time separated by ~2 hours, the physiologic/pharmacologic state of the subject may have changed complicating interpretation of the results; 3) if one is interested in how two receptor systems interact, a study involving a pharmacologic challenge would require four PET scans, two separate baseline scans (one for each radioligand) and two challenge scans. Such a protocol currently would require multiple days to perform.
IONIZING RADIATION AND RADIOACTIVE SUBSTANCES
A transmission scan will be performed for measurement of attenuation factors. The exposure from this procedure is estimated to be less than 20 mR to the brain and lens of the eye.
Subjects will be injected with 14 mCi [11C]nBMP and 14 mCi [11C]PMP.
INVOLVEMENT OF HUMAN SUBJECTS
A brief medical and neurologic examination will be done.
PET imaging will take approximately four hours. Subjects will be positioned in the PET scanner where they will undergo the transmission scan. Subjects will be studied using one of two protocols. 1) A vein will be catheterized to allow for radiopharmaceutical injection. A 10 ml blood sample will be obtained from this line or by venipuncture. The subject will be injected with 14 mCi of [11C]nBMP. Imaging will begin immediately and continue for 60 minutes. One hour later 14 mCi [11C]PMP will be injected. Imaging will begin immediately and continue for 60 minutes. OR 2) A vein will be catheterized to allow for radiopharmaceutical injection. A radial artery will be catheterized for withdrawal of blood samples. The subject will be injected with 14 mCi of [11C]nBMP. Arterial blood sampling and dynamic PET imaging will begin simultaneously. Approximately fifteen minutes post-injection the subject will be injected with 14 mCi of [11C]PMP. Imaging and blood sampling will continue for sixty minutes. An arterial input function will be generated from the arterial blood samples and coupled with the dynamic PET images to generate quantitative images. At the completion of the PET imaging, the catheters will be removed and the subject will be released.
RISKS
Low-level radiation exposure
Cannulation of the radial artery
Cannulation of a cutaneous vein
Idiosyncratic/allergic reaction to the study radiopharmaceutical
PRIVACY/CONFIDENTIALITY/CONSENT
Subjects will not be personally identified during presentation or write-up of the data. PET research data has limited accessibility.
Written informed consent will be obtained from all subjects.
Institutional Review Board (IRB) Review:
Type of Review: Full Board
Approving Institution: University of Michigan Hospitals
Most recent approval: 07/31/02
IRB approval number: 1999-0684
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 4
Reporting period for number of human subjects:
Fiscal Year 2002
Type(s) of Human Subjects Involvement:
OBJECTIVES AND METHODOLOGY
The goal of this research is to develop and test methods to study multiple neuropharmacological parameters simultaneously using quantitative positron emission tomography (PET). Currently, we are completing the initial phase of this research proving the feasibility of doing dual tracer studies which allow studies that currently take 4 hours to be completed in 2 hours. Results appear promising and demonstrate that multiple neuropharmacological measures can be made in a single scanning session. Previously, we studied two different pairs of tracers under baseline conditions [11C]flumazenil ([11C]FMZ) & [11C]dihydrotetrabenazine ([11C]DTBZ) or [11C]FMZ & [11C]Methylpiperidinyl Propionate ([11C]PMP). The goal of this current project is to extend this work to perform validation studies following a pharmacological intervention demonstrating both sensitivity and specificity to particularly interventions. We have chosen two known interventions to validate dual-tracer studies using these same two tracer pairs. These interventions will validate sensitivity and specificity to pharmacological intervention using two challenges already studies in our facility, 1) administration of a partial blocking dose of unlabeled flumazenil (effecting only [11C]FMZ binding measures) or administration of physostigmine, an acetylcholinesterase inhibitor (effecting only ([11C]PMP hydrolysis measures).
Brain functions are modulated by connections between cerebral structures and interactions among different neurochemical systems. Disease processes often involve multiple cerebral structures and different neurochemical systems that interact with each other. Changes in a neurochemical system in one part of the brain consequently affect other neurochemical systems in different areas of the brain. The significance of this work centers on the concept that, rather than examining particular aspects of the working brain in isolation, we would like to validate methods that can provide a broader more global view of cerebral function. We wish to examine interactions between various neuropharmacological systems and to study effects that one neurotransmitter/receptor system has on another, not just examine one component at a time without seeing how this system fits into the overall workings of the human brain. Our work to date has centered on demonstrating that dual scans are indeed feasible and on optimizing the data acquisition and analysis protocols for such studies. The significance of this particular aspect of the project relates to the overall goal of studying how two different neuroreceptor systems interact. One way to do this is to perturb the systems by giving a pharmacologic challenge. Here we are performing validation studies to demonstrate that when known pharmacologic challenges are given ("cold" flumazenil or physostigmine) we can appropriately separate these effects based on the measured PET data.
IONIZING RADIATION AND RADIOACTIVE SUBSTANCES
A transmission scan will be performed for measurement of attenuation factors. The exposure from this procedure is estimated to be less than 20 mR to the brain and lens of the eye.
Subjects involved in this research project will be injected according to one of the following injection scenarios:
1. [11C]FMZ + [11C]PMP (baseline)
[11C]FMZ + [11C]PMP (physostigmine intervention) OR
2. [11C]FMZ + [11C]PMP (baseline)
[11C]FMZ + [11C]PMP (Romazicon intervention) OR
3. [11C]FMZ + [11C]DTBZ (baseline)
[11C]FMZ + [11C]DTBZ (Romazicon intervention)
INVOLVEMENT OF HUMAN SUBJECTS
A brief medical and neurologic examination will be done.
PET imaging will take approximately four hours. A radial artery and a vein will be catheterized to allow for blood sampling and radiopharmaceutical injection. Subjects will be positioned in the PET scanner and the transmission scan will be done. The subject will be injected with 12 mCi of [11C]FMZ. Arterial blood sampling and dynamic PET imaging will begin simultaneously. Approximately fifteen minutes post-injection the subject will be injected with 12 mCi [11C]DTBZ OR 12 mCi [11C]PMP. Imaging and blood sampling will continue for sixty minutes. When this first set of studies is completed a pharmacologic intervention will be administered. If a subject was injected with [11C]DTBZ the pharmacologic intervention will be the administration of cold flumazenil. For half of the subjects injected with [11C]PMP the pharmacologic intervention will be physostigmine. For the other half, the intervention will be cold flumazenil. A second set of identical PET scans will be performed. At the completion of the PET imaging, the catheters will be removed the subject will be released. An arterial input function will be generated from the arterial blood samples and coupled with the dynamic PET to generate quantitative images.
RISKS
Low-level radiation exposure
Cannulation of the radial artery
Cannulation of a cutaneous vein
Idiosyncratic/allergic reaction to the study radiopharmaceutical
PRIVACY/CONFIDENTIALITY/CONSENT
Subjects will not be personally identified during presentation or write-up of the data. PET research data has limited accessibility.
Written informed consent will be obtained from all subjects.
Institutional Review Board (IRB) Review:
Type of Review: Full Board
Approving Institution: University of Michigan Hospitals
Most recent approval: 01/24/02
IRB approval number: 99-068
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 2002
Type(s) of Human Subjects Involvement:
OBJECTIVES & METHODOLOGY
The general goal of this research is to develop and test methods to study multiple neuropharmacological parameters simultaneously using quantitative positron emission tomography (PET). Currently, if one is interested in examining two distinct neuropharmacologic measures with PET, one has to perform two separate PET studies typically spaced in time by about 2 hours. An overall duration for such a study requires approximately 4 hours. The specific goal of this research is to evaluate the feasibility of performing dual-tracer PET studies, where two different PET radiotracers, each designed to provide information about a specific neuropharmacological system or parameter, are injected only 10-30 minutes apart. In this approach, only a single "overlapping" PET study is acquired and the duration of the entire study is shortened by 2 hours. Kinetic modeling and data analysis procedures have been developed and implemented, and computer simulations have been performed proving theoretical feasibility of extracting specific information about each radioligand from the single-acquisition dual-tracer PET scan. The preliminary phases of this research project has been completed and now we are at the point of requiring studies in normal human subjects to prove practical feasibility of the method.
Brain functions are modulated by connections between cerebral structures and interactions among different neurochemical systems. Disease processes often involve multiple cerebral structures and different neurochemical systems which interact with each other. Changes in a neurochemical system in one part of the brain consequently affect other neurochemical systems in different areas of the brain. The significance of this work centers on the concept that, rather than examining particular aspects of the working brain in isolation, we would like to validate methods which can 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 examine one component at a time without seeing how this system fits into the overall workings of the human brain. If one has to perform two PET studies to examine two distinct neuropharmacologic measures, several obvious limitations arise: 1) the long study times make it extremely difficult to study certain patient populations; 2) when obtaining neuropharmacologic measures at two distinct points in time separated by ~2 hours, the physiologic/pharmacologic state of the subject may have changed complicating interpretation of the results; 3) if one is interested in how two receptor systems interact, a study involving a pharmacologic challenge would require four PET scans, two separate baseline scans (one for each radioligand) and two challenge scans. Such a protocol currently would require multiple days to perform. With the proposed dual-tracer scanning capability, even this complicated study could be performed in a single half-day session. Until recently, the statistical quality of PET data did not justify these types of studies to be performed, and thus such challenging research protocols were typically not even considered. Approximately five years ago, methodology was first developed to perform 3-dimensional PET scanning which offers a great increase in scan sensitivity. Over the past few years, research in 3-D PET coupled with advances in computer processing power and data storage and handling capabilities have made 3-D PET a reality. 3-D PET scanning is routinely available at our facility, thus making multiple PET scan protocols fully plausible.
IONIZING RADIATION & RADIOACTIVE SUBSTANCES
Subjects will have a 10 - 15 minute transmission scan performed for measurement of attenuation factors for the PET scan. The additional exposure from this procedure is estimated to be less than 20 mR to the brain and lens of the eye.
Subjects involved in this research project will be injected via venous catheter with one bolus injection of [11C]flumazenil ([11C]FMZ), and one bolus injection of [11C]dihydrotetrabenazine ([11C]DTBZ) OR [11C]Methylpiperidinyl Propionate ([11C]PMP) . The injection of these radiotracers allows for PET imaging of benzodiazepine receptor binding, monoamine storage vesicles and acetylcholinesterase, respectively.
Subjects are exposed to ionizing radiation in the form of gamma rays. The biological effect of the radiation from the injection of [11C]FMZ is approximately 0.345 rem, from [11C]DTBZ approximately 0.548 rem, and 0.470 rem from the [11C]PMP. The cumulative effective dose and risk of this level of exposure is less than that of two CT exams of the chest.
INVOLVEMENT OF HUMAN SUBJECTS
General Procedures
Thirty normal subjects over the age of 18 will be studied. Subjects will be studied at random without regard to gender, ethnicity or race. Women of child-bearing potential will be recruited for this study, but pregnant or breast-feeding females will be excluded. Subjects will undergo a brief medical examination and physical history to rule out any underlying abnormalities. Subjects will provide written informed consent prior to enrollment in this project. Subjects will participate for approximately three hours in a PET imaging session of the brain. A radial artery and an antecubital vein will be catheterized to allow for blood sampling and radiopharmaceutical injection, respectively. Subjects will be positioned in the PET scanner where they will undergo a brief transmission scan to calculate attenuation correction factors. The subject will be injected via the intravenous catheter with 15 mCi of [11C]flumazenil ([11C]FMZ). Arterial blood sampling and dynamic PET imaging will begin simultaneously. Fifteen to thirty minutes post-injection the subject will be injected with 15 mCi [11C]dihydrotetrabenazine ([11C]DTBZ) OR 15 mCi [11C]Methylpiperidinyl Propionate ([11C]PMP). Fifteen subjects will be studied with [11C]FMZ and [11C]DTBZ and fifteen subjects will be studied with [11C]FMZ and [11C]PMP. For each group the order of injections will be counter-balanced. Imaging and blood sampling will continue for another sixty minutes. At the completion of the PET imaging, the catheters will be removed and the subject will be asked to void and will be instructed to increase fluid intake and to urinate frequently for the remainder of the afternoon. An arterial input function will be generated from the arterial blood samples and coupled with the dynamic PET images through compartmental modeling to generate quantitative images. The subjects' data will be referenced by hospital registration number. The subject will not be identified personally in any write-ups or presentations of the data.
Risks
Low-level radiation exposure
The biologic effects of this level of exposure are judged to be minimal. The effective dose and risk of the level of exposure is less than that from 2 CT exams of the chest. There is no documented biologic effect of radiation exposure at these levels, although statistically undetectable increases in the incidence of certain malignancies cannot be entirely excluded. There are no alternatives to the use of PET for non-invasive delineations of benzodiazepine receptor binding, monoaminergic neurons or acetylcholinesterase. The risks are minimized by administering the smallest radiotracer doses acceptable for acquiring the necessary PET data, and by strict adherence to accepted protocols for dispensing and administration of radiopharmaceuticals. There should be no significant effect on fertility potential arising from these studies. Pregnant or breast-feeding females will be excluded from the study.
Cannulation of the radial artery
The likelihood of a complication (ischemic, hemorrhagic, infectious) from short-term percutaneous cannulation of the radial artery is small (substantially less than 1 in 1000). Local anesthesia and sterile technique are utilized to minimize discomfort and the risk of infection. Arterial cannulation is performed by an individual trained and experienced in the technique. The patency of the radial artery and adequacy of local hemostasis are verified by the PET technologists at the conclusion of the imaging session. A physician is immediately available throughout the imaging session for evaluation of potential complications. In the unlikely event of an ischemic complication, medical treatment with the use of either thrombolytic drugs and/or vascular surgery would be initiated. Infectious complications will be managed with the parenteral administration of antibiotics. The medical and surgical management of potential radial artery occlusion are expected to be successful in mitigating major ischemic injury to the hand. There are no alternative procedures to obtain the arterial tracer input functions necessary for quantification of the PET data. We have utilized this procedure for PET imaging protocols for over 10 years without serious complication. Any significant complications arising from the radial cannulation will be noted and reported to the IRB.
Cannulation of a cutaneous vein
The likelihood and severity of a complication (infectious, hemorrhagic) are minimal. Cannulation is performed by experienced personnel with aseptic technique. Infectious complications will be managed by parenteral administration of antibiotics. The subjects are instructed to contact one of the investigators (phone numbers provided on consent form), their personal physician, or the emergency room for evaluation of any potential adverse effect. There is no alternative to intravenous access for the administration of radiotracers for PET imaging.
Idiosyncratic/allergic reaction to the study radiopharmaceutical
The likelihood of a reaction to tracer administration is low due to the small chemical amounts of tracer administered. Subjects are continuously monitored and observed during the PET imaging session by a certified nuclear medicine technologist. A physician is immediately available during all PET imaging sessions and a "crash cart" is available in the PET imaging suite for emergency use. Allergic reactions will be treated with steroids, antihistamines and epinephrine, all of which are immediately available in the PET imaging suite. In the unlikely event of a severe allergic response, the subject will be hospitalized for observation following initial emergency treatment. There are no alternatives to the use of these radiopharmaceuticals for the PET measurements to be made. These measures are expected to control any allergic reaction encountered. All adverse reactions will be reported to the IRB.
Privacy/Confidentiality/Consent
A research subject will not be personally identified during presentation or write-up of the data. PET research data has limited accessibility.
Written informed consent will be obtained after the procedure has been described to the subject in the Division of Nuclear Medicine by a researcher or technologist associated with the project.
Institutional Review Board (IRB) Review:
Type of Review: Full Board
Approving Institution: University of Michigan Hospitals
Most recent approval: 09/20/01
IRB approval number: 1999-0682
Explanation of IRB approval:
This IRB project will not be renewed. The subjects reported for this fiscal year were done prior to 09/30/02. This subproject will be deleted from the HSRD next year.
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 2002
Type(s) of Human Subjects Involvement:
Objectives & Methodology
The primary goal of this research is to evaluate and to validate a new approach for performing PET studies that have the aim of quantifying effects of a neuropharmacological intervention or challenge. Current protocols used to measure effects of an intervention require two PET scans, a baseline scan followed by the intervention and then a second scan. The proposed new method involves performing a single PET study with the intervention given approximately half way through the scan. The difficulty is that unless the radiotracer has very rapid binding kinetics, obtaining multiple measures of the neuropharmacological parameter of interest under both baseline and challenge conditions can not be done within the time frame of a single PET scan. The majority of PET tracers selected for these studies are labeled with [11C], which has a 20 min half-life. The previous methods require full equilibration of the radiotracer to occur in the brain prior to obtaining each of the two binding measures, and thus two separate studies are performed, separated typically by 2 hours. The proposed method does not require complete equilibration, but takes into account the kinetic information during the equilibrating phase of studies, enabling both baseline and "challenge" measures to be made during the much shorter period of time dictated by the half-life of the radiotracer. We propose to perform studies comparing intervention studies using the new single-scan protocol with the conventional two scan approach.
A potentially very promising area of PET research involves examining the interaction between multiple neurotransmitter systems. Neuropharmacological "challenge" or "perturbation" studies may be designed to study the effect of an intervention on some aspect of a neurotransmitter system. For example, amphetamine challenges, which cause dopamine release, have been used to study the effect of endogenous dopamine levels on post-synaptic dopamine D2 binding as measured by [11C]raclopride. Challenge studies have also been used to study effects of one transmitter on a second system. For example, one can examine glutamate modulation of dopamine binding measure by PET with [11C]raclopride. Such experimental designs are not limited to pharmacological perturbation. Recently, it has been demonstrates that behavioral or cognitive challenge can induce changes in neurotransmitter levels that can be measured by PET. However, the majority of any of the above types studies have used multiple radiotracer administrations and required separate scans under "baseline" and "stimulus" conditions. In this work we are developing, optimizing, and validating methods of performing such challenge studies using only a single tracer administration, thus saving both time (subject as well as investigator), effort, money, and radiation exposure to the volunteer.
Ionizing Radiation and Radioactive Substances
Subjects will have a brief transmission scan performed for measurement of attenuation factors. The exposure from this procedure is estimated to be less than 20 mR to the brain and lens of the eye.
Subjects will be injected via venous catheter with one injection of 18 mCi [11C]flumazenil or two injections of 15 mCi of [11C]flumazenil. The injection of this radiotracer allows for PET imaging of benzodiazepine receptor binding.
Involvement of Human Subjects
A brief medical and neurologic examination will be performed.
Subjects will participate for approximately five hours in a PET imaging session. An antecubital vein will be catheterized to allow for radiopharmaceutical injection. Subjects will be positioned in the PET scanner where they will undergo a transmission scan. Subjects will be studied according to one of four injection scenarios: 1) subject is injected via the intravenous catheter with 18 mCi of [11C]flumazenil; 2) subject is injected via the venous catheter with 2 injections of 15 mCi of [11C]flumazenil two hours apart; 3) subject is injected via the intravenous catheter with 18 mCi of [11C]flumazenil with a pharmacologic intervention 40 - 50 minutes after injection; 4) subject is injected via the venous catheter with 2 injections of 15 mCi of [11C]flumazenil injected two hours apart with a pharmacologic intervention introduced between the two injections. At the completion of the PET imaging session(s), the catheter will be removed.
RISKS
Low-level radiation exposure: the biologic effects of this level of exposure are minimal
Cannulation of a cutaneous vein: the likelihood and severity of a complication (infectious, hemorrhagic) are minimal
Idiosyncratic/allergic reaction to the study radiopharmaceutical: the likelihood of a reaction to tracer administration is low due to the small chemical amounts of tracer administered.
PRIVACY/CONFIDENTIALITY/CONSENT
A research subject will not be personally identified during presentation or write-up of the data. PET research data has limited accessibility.
Comprehensive written informed consent will be obtained from all subjects.
Institutional Review Board (IRB) Review:
Type of Review: Full Board
Approving Institution: University of Michigan Hospitals
Most recent approval: 09/20/01
IRB approval number: 1999-0685
Explanation of IRB approval:
This IRB project will not be renewed. The recruitment and study of subjects under this IRB is complete. This subproject will be deleted from the HSRD next year.
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 19
Reporting period for number of human subjects:
Fiscal Year 2002
Type(s) of Human Subjects Involvement:
OBJECTIVES AND METHODOLOGY
The primary goal of this research is to evaluate and to validate a new approach for performing PET studies that have the aim of quantifying effects of a neuropharmacological intervention or challenge. Current protocols used to measure effects of an intervention require two PET scans, a baseline scan followed by the intervention and then a second scan. The proposed new method involves performing a single PET study with the intervention given approximately half way through the scan. The difficulty is that unless the radiotracer has very rapid binding kinetics, obtaining multiple measures of the neuropharmacological parameter of interest under both baseline and challenge conditions can not be done within the time frame of a single PET scan. The majority of PET tracers selected for these studies are labeled with [11C], which has a 20 min half-life. The previous methods require full equilibration of the radiotracer to occur in the brain prior to obtaining each of the two binding measures, and thus two separate studies are performed, separated typically by 2 hours. The proposed method does not require complete equilibration, but takes into account the kinetic information during the equilibrating phase of studies, enabling both baseline and "challenge" measures to be made during the much shorter period of time dictated by the half-life of the radiotracer. We propose to perform studies comparing intervention studies using the new single-scan protocol with the conventional two scan approach.
A potentially very promising area of PET research involves examining the interaction between multiple neurotransmitter systems. Neuropharmacological "challenge" or "perturbation" studies may be designed to study the effect of an intervention on some aspect of a neurotransmitter system. For example, amphetamine challenges, which cause dopamine release, have been used to study the effect of endogenous dopamine levels on post-synaptic dopamine D2 binding as measured by [11C]raclopride. Challenge studies have also been used to study effects of one transmitter on a second system. For example, one can examine glutamate modulation of dopamine binding measure by PET with [11C]raclopride. Such experimental designs are not limited to pharmacological perturbation. Recently, it has been demonstrates that behavioral or cognitive challenge can induce changes in neurotransmitter levels that can be measured by PET. However, the majority of any of the above types studies have used multiple radiotracer administrations and required separate scans under "baseline" and "stimulus" conditions. In this work we are developing, optimizing, and validating methods of performing such challenge studies using only a single tracer administration, thus saving both time (subject as well as investigator), effort, money, and radiation exposure to the volunteer.
IONIZING RADIATION AND RADIOACTIVE SUBSTANCES
A brief transmission scan will be performed for measurement of attenuation factors for the PET scan. The additional exposure from this procedure is estimated to be less than 20 mR to the brain and lens of the eye.
Subjects will be injected via venous catheter with one injection of 18 mCi [11C]carfentanil or two injections of 15 mCi of [11C]carfentanil to allow for the PET imaging studies.
INVOLVEMENT OF HUMAN SUBJECTS
A brief medical and neurologic examination will be done.
PET imaging will take up to five hours to complete. An antecubital vein will be catheterized to allow for radiopharmaceutical injection. Subjects will be positioned in the PET scanner for the transmission. Subjects will be studied according to one of four injection scenarios: 1) subject will be injected with 18 mCi of [11C]carfentanil; 2) subject will be injected with 2 injections of 15 mCi of [11C]carfentanil; 3) subject will be injected with 18 mCi of [11C]carfentanil; with a pharmacologic intervention; 4) subject will be injected with 2 injections of 15 mCi of [11C]carfentanil with a pharmacologic intervention between the injections. PET imaging will begin at the time of radiotracer injection. At the completion of the PET imaging session(s), the catheter will be removed and the subject will be finished.
RISKS
Low-level radiation exposure: the biologic effects of this level of exposure are judged to be minimal
Cannulation of a cutaneous vein: the likelihood and severity of a complication (infectious, hemorrhagic) are minimal.
Idiosyncratic/allergic reaction to the study radiopharmaceutical: the likelihood of a reaction to tracer administration is low due to the small chemical amounts of tracer administered.
PRIVACY/CONFIDENTIALITY/CONSENT
A research subject will not be personally identified during presentation or write-up of the data. PET research data has 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.