Quantitation of Human Cerebral Nicotinie Receptors With 2[18F]FA-85380 and PET Healthy Non-smokers and Ex-Smokers and in Heavy and Light Situational Smokers
Condition: Nicotine Addiction
MeSH terms: Tobacco Use Disorder
Study type: Observational

Summary: 
      Background:

      - Central nicotinic acetylcholine receptors (nAChRs) are primary targets for the action of
      nicotine. In addition to being involved in tobacco dependence, they are also involved in a
      variety of brain disorders, including Alzheimer's and Parkinson's diseases. Researchers are
      interested in developing better ways to study the action of nAChRs to improve treatments for
      smoking cessation and other problems affected by these receptors. These new study methods may
      involve different approaches to positron emission tomography (PET) scanning, which can show
      brain activity related to nAChRs.

      Objectives:

      - To evaluate appropriate and useful doses of radiotracers used in PET scanning of nAChRs in
      the brains of nonsmokers/former smokers, light smokers, and heavy smokers.

      Eligibility:

      - Individuals between 18 and 50 years of age who fall into one of the following groups: (1)
      nonsmokers or former smokers who have not smoked for the past 2 years, (2) light/situational
      smokers, or (3) heavy smokers (at least 15 cigarettes/day for the past 2 years).

      Design:

        -  Each participant will undergo up to three PET studies, given approximately1 month apart.
           Each study will take approximately 8 hours to complete.

        -  Participants will provide urine and breath samples before the study and at the start of
           the study, which will be tested for chemicals that may interfere with the study.

        -  Depending on the study, some of the smoking participants may receive a nicotine patch to
           wear during the PET scan.

        -  On the day of the study, participants will receive a dose of a radiotracer (a drug used
           in PET scanning) given either as a single injection or as an injection followed by a
           continuous infusion, and will have a series of PET scans over the next 7 hours and
           provide blood samples during that time.

        -  Participants will return for a follow-up visit 1 month after the end of the study.
    

Detailed description: 
      Background: Central nicotinic acetylcholine receptors (nAChRs) mediate a variety of brain
      functions and have been implicated in the pathophysiology of Alzheimer's and Parkinson's
      diseases, other CNS disorders (Tourette's syndrome, epilepsy, etc.), and nicotine dependence.
      These receptors are the primary target for the action of nicotine, which is believed to cause
      tobacco dependence. The ability to quantitatively image nAChRs with PET in humans would allow
      scientists to monitor the nAChRs in vivo during nicotine dependence and smoking cessation and
      to determine the receptor occupancy by nicotine for different types of nicotine replacement
      therapy (NRT). Recently completed studies demonstrated the feasibility of imaging nAChRs in
      the human brain with 2[18F]FA-85380 and showed that each participant could receive up to 4
      injections of 5 mCi/70 kg without exceeding dosimetry limits imposed by the FDA and the NIH
      Radiation Safety Committee.

      Scientific Goal: The aims of the proposed study are 1) to compare the total volumes of
      distribution for 2[18F]FA-85380 and volumes of distribution for specific binding compartment
      (an estimate of nAChR densities) in brains of light and heavy smokers and 2) to develop a
      simplified PET procedure that is more comfortable for the human participants and that
      maintains the ability to accurately quantify nAChR binding in vivo.

      Study Population: Healthy adult participants (non-smokers or exsmokers and light
      (situational) and heavy smokers), males and females between 18 and 50 years of age, will be
      recruited for this study. The goal is to complete studies of 12 controls (non-smokers or
      exsmokers), 12 light smokers and 12 heavy smokers.

      Experimental Design and Method: After being medically cleared and giving informed consent,
      each participant will undergo up to three PET studies. In each study, the participant will
      receive a 5 mCi/70 kg dose of the radioligand, 2[18F]FA-85380-Injection. For one of the
      studies, the participants who smoke will receive nicotine by a nicotine patch (Nicoderm),
      applied approximately 4 h before the scan. The patch will be removed 12 h after it is
      applied. For two studies (one without and one with nicotine), participants who smoke will
      receive the radioligand as a bolus injection. Six of the participants who do not currently
      smoke (control group) will receive the radioligand as a bolus injection twice without
      nicotine either time. For the third study, all participants will receive the radioligand as a
      bolus injection followed by a continuous infusion (bolus injection/infusion combination). Six
      of the participants who do not currently smoke (control group) will receive the radioligand
      as a bolus plus infusion injection twice. For each study, a series of brain PET scans will be
      acquired for 8 h beginning at the time of the injection. The data from the PET scans without
      and with nicotine patch (smokers only) will be used to determine the total and non-specific
      accumulation of radioactivity in the brain. The data from the equivalent two PET scans for
      the controls will be used to determine the test-retest reliability of the measure. The data
      from the PET scans acquired from the bolus/infusion paradigm will be used to demonstrate the
      feasibility of a shorter scanning period for quantitation studies. It is anticipated that
      several of the participants will choose not to continue after the first scan. The study
      design accommodates this expectation.

      Benefits to participants and/or society: This protocol will provide no direct benefits to the
      research participants other than routine medical screening and attention from the research
      staff. The knowledge gained in this study may lead to the availability of an agent for
      external monitoring of nAChRs using PET. This agent would be a valuable tool for determining
      the dynamics of nAChRs in nicotine dependence and smoking cessation.

      Risks to participants: There are risks related to the PET scans in general, involving
      exposure to radiation, arterial catheterization and venous catheterization. In addition,
      there are risks related to the administration of this radiopharmaceutical and from exposure
      to nicotine. Medical supervision will be provided throughout the study. A plan for monitoring
      potential side effects of this radiotracer is given.
    

Keywords: Receptor Up-Regulation; Smoking; Nicotine; Neuroimaging