Specific PET Radioligand Binding to Translocator Protein
Condition: Baseline; Blocking Receptor Binding
Study type: Interventional
Phase: Phase 1

Summary: 
      Background:

      - A brain protein called translocator protein (TSPO) shows changes in some brain diseases. A
      radioactive drug called 11C-(R)-PK 11195 is used to take pictures of TSPO using a camera
      called positron emission tomography (PET). Researchers want to find out how well 11C-(R)-PK
      11195 takes the pictures.

      Objective:

      - To evaluate the radioactive chemical 11C-(R)-PK 11195.

      Eligibility:

      - Healthy volunteers ages 18-55.

      Design:

        -  Participants will be screened with a medical exam.

        -  Participants will have scans at up to 4 visits.

             -  PET scan using 11C-(R)-PK 11195:

                  -  A small tube (catheter) will be put into an artery at the wrist or elbow, by a
                     needle. The needle will be removed, leaving only the catheter in the artery.
                     Blood samples will be taken through this catheter.

                  -  Another catheter will be placed into a vein in the arm or hand.

                  -  11C-(R)-PK 11195 will be injected through the second catheter.

                  -  The PET scanner is shaped like a doughnut. Participants will lie on a bed that
                     slides in and out of it. They may get a plastic mask for their face and head.

             -  Participants will receive a dose of emapunil by mouth. Participants will then have
                another PET scan.

             -  Participants may have a magnetic resonance imaging (MRI) scan. The MRI scanner is a
                metal cylinder surrounded by a magnetic field. The participant will lie on a table
                that can slide in and out of the cylinder. Participants will get earplugs for the
                loud knocking noises.

        -  After each scan, participants will get a follow-up phone call. Two to seven days after
           taking emapunil, participants will return for a follow-up visit.
    

Detailed description: 
      Objective:

      The 18kDa Translocator Protein (TSPO, formerly known as the peripheral benzodiazepine
      receptor (PBR)) is expressed in activated microglia and reactive astrocyte. It has therefore
      been used as an imaging target for positron emission tomography (PET) to investigate diseases
      involving microglial activation and/or macrophage recruitment, such as multiple sclerosis,
      herpes encephalitis, Parkinson s disease, Alzheimer s disease and ischemic stroke. The vast
      majority of PET studies reported to date have used 11C-(R,S) and 11C-(R)-PK 11195, a
      3-isoquinolinecarboxamide antagonist, with nanomolar affinity for TSPO. Several second
      generation radioligands, including 11C-PBR28, 11C-DPA-713, and 11C-ER176 have been developed.
      Although these ligands have greater signal to noise (specific to nondisplaceable uptake)
      ratio than 11C-(R)-PK 11195,their binding to TSPO is affected by a single nucleotide
      polymorphism (SNP). Specific to nondisplaceable ratio of 11C-PBR28 has recently been
      reported. However, no one has ever measured the specific to nondisplaceable ratio of other
      TSPO radioligands including 11C-(R)-PK 11195, 11C-DPA-713 and 11C-ER176 in human subjects. In
      addition, differences in this binding site between species preclude comparisons based on
      studies in animals. The purposes of this study are to measure the signal to noise ratio
      (i.e., ratio of specific to non-displaceable uptake) of 11C-(R)-PK 11195, 11C-ER176 and
      11C-DPA-713 in human subjects with two scans in each subject: at baseline and after emapunil,
      an agonist at the TSPO site and a putative anxiolytic based on studies in animals and in
      humans and study the effect of the SNP on the in vivo specific binding of the PET ligands.

      Study population:

      75 healthy volunteers in total aged 18 to 55 years. Of these, 25 will have 11C-(R)-PK 11195,
      25 have 11C-DPA-713 scans, and 25 have 11C-ER176.

      Design:

      Healthy volunteers (n = up to 25) will have two scanning sessions using 11C-(R)-PK 11195: a)
      baseline i.e., medication-free and b) blocking i.e. with medication. For blocking, we will
      give one oral dose of emapunil (15 or 90 mg), about 1.5 hours before the second injection of
      the radioligand. Both scanning sessions would include an arterial line and measurement of the
      input function of parent radioligand separated from radiometabolites as well as plasma free
      fraction of radioligand. Additional 25 healthy volunteers will have two scanning sessions
      using 11C-DPA-713 in the same design, one baseline and another after one oral dose of
      emapunil. An additional 25 healthy volunteers will have two scanning sessions using 11C-ER176
      in the same design, one baseline and another after one oral dose of emapunil. The total
      number of participants is 75 (= 25 + 25 + 25)

      Outcome measures:

      Baseline scans measure total binding i.e., total distribution volume (V[T]). By applying the
      Lassen plot, combined data from both baseline scans and those with administration of emapunil
      measure nonspecific binding i.e., nondisplaceable distribution volume (V[ND]). From these
      V[T] and V[ND] values, specific-to-nondisplaceable ratios will be calculated as (V[T] V[ND])
      / V[ND[ and the influence of the SNP to specific binding, V[S] = V[T] - VND will also be
      studied.
    

Intervention name(s): Emapunil; PET
Intervention type(s): Drug; Device
Intervention description(s): Single peroral administration; Positron emission tomography, which creates images by detecting radioactivity.
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Diagnostic
Keywords: Health Humans; Receptor Occupancy