Evaluation of a Novel Positron Emission Tomography (PET Radiotracer for TARP Gamma-8

Study Overview
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Brief Summary
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Objective Ionotropic glutamate receptors are ligand-gated ion channels responsible for most of the excitatory neurotransmission in the mammalian central nervous system (CNS). Based on pharmacology, they have been grouped into three subtypes-NMDA, AMPA and kainate. In recent years it has become apparent that the receptors do not function alone, but in the company of auxiliary proteins that regulate their activity [1]. Some of these have been shown to modulate AMPA receptor trafficking, gating and pharmacology and are classified as transmembrane AMPA receptor regulatory proteins, or TARPs ( >=-2, >=-3, >=-4, >=-5, >=-7, and >=-8). Genetic data indicate a possible role of TARPs in schizophrenia, depression, epilepsy, neuropathic pain, and bipolar disorder [1]. In a preclinical collaboration with Eli Lilly, we developed a promising radioligand, 18F-TARP252 to image TARP >=-8 using positron emission tomography (PET). This protocol covers three phases: Phase 1: kinetic brain imaging to quantify TARP >=-8 in brain relative to concurrent measurement of the parent radioligand in arterial plasma; Phase 2: if 18F-TARP252 is successful in Phase 1, we will estimate the radiation-absorbed doses by performing whole body imaging; Phase 3: test-retest analysis of brain binding relative to concurrent measurement of the parent radioligand in arterial plasma. Study Population Healthy adult female and male volunteers (n=22, ages 18 - 55) will undergo brain imaging. An additional eight healthy volunteers will undergo whole body dosimetry analysis. Design For quantification of TARP >=-8, 22 healthy controls will have brain PET imaging using 18F-TARP252 and an arterial line. Some of them will have a test-retest scan. Eight additional subjects will have a whole body PET scan for dosimetry. For dosimetry, no arterial line will be used. Outcome Measures To assess quantitation of TARP >=-8 with 18F-TARP252, we will primarily use two outcome measures: the identifiability and time stability of distribution volume calculated with compartmental modeling. In test-retest study, we will calculate the retest variability. We will assess whole-body biodistribution and dosimetry of 18F-TARP252 by calculating doses to organs and effective dose to the body.

Detailed Description
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Objective Ionotropic glutamate receptors are ligand-gated ion channels responsible for most of the excitatory neurotransmission in the mammalian central nervous system (CNS). Based on pharmacology, they have been grouped into three subtypes-NMDA, AMPA and kainate. In recent years it has become apparent that the receptors do not function alone, but in the company of auxiliary proteins that regulate their activity [1]. Some of these have been shown to modulate AMPA receptor trafficking, gating and pharmacology and are classified as transmembrane AMPA receptor regulatory proteins, or TARPs ( >=-2, >=-3, >=-4, >=-5, >=-7, and >=-8). Genetic data indicate a possible role of TARPs in schizophrenia, depression, epilepsy, neuropathic pain, and bipolar disorder [1]. In a preclinical collaboration with Eli Lilly, we developed a promising radioligand, 18F-TARP252 to image TARP >=-8 using positron emission tomography (PET). This protocol covers three phases: Phase 1: kinetic brain imaging to quantify TARP >=-8 in brain relative to concurrent measurement of the parent radioligand in arterial plasma; Phase 2: if 18F-TARP252 is successful in Phase 1, we will estimate the radiation-absorbed doses by performing whole body imaging; Phase 3: test-retest analysis of brain binding relative to concurrent measurement of the parent radioligand in arterial plasma. Study Population Healthy adult female and male volunteers (n=22, ages 18 - 55) will undergo brain imaging. An additional eight healthy volunteers will undergo whole body dosimetry analysis. Design For quantification of TARP >=-8, 22 healthy controls will have brain PET imaging using 18F-TARP252 and an arterial line. Some of them will have a test-retest scan. Eight additional subjects will have a whole body PET scan for dosimetry. For dosimetry, no arterial line will be used. Outcome Measures To assess quantitation of TARP >=-8 with 18F-TARP252, we will primarily use two outcome measures: the identifiability and time stability of distribution volume calculated with compartmental modeling. In test-retest study, we will calculate the retest variability. We will assess whole-body biodistribution and dosimetry of 18F-TARP252 by calculating doses to organs and effective dose to the body.

Official Title
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Evaluation of a Novel Positron Emission Tomography (PET Radiotracer for TARP Gamma-8

Conditions
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Healthy Volunteers

Intervention / Treatment
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* Procedure: Brain Imaging (PET)
* Procedure: Aterial Line
* Procedure: Blood Sampling


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Age 18 - 55 (including 18 and 55). Able to give written informed consent. Healthy Enrolled in 01-M-0254 EXCLUSION CRITERIA: Any current Axis I diagnosis. Clinically significant laboratory abnormalities. Positive HIV test. Unable to have an MRI scan. History of neurologic illness or injury with the potential to affect study data interpretation. Recent exposure to radiation related to research (i.e. PET from other research) that, when combined with this study, would be above the allowable limits. Inability to lie flat on camera bed for at least two hours. Pregnancy or breast feeding. Able to get pregnant but does not use birth control. Drug/alcohol abuse or dependence Exclusion criteria for the dosimetry subjects are the same as reported above, with the exception of MRI contraindications, because an MRI will not be performed in these subjects.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Procedure: Brain Imaging (PET)|nan|
|Procedure: Aterial Line|nan|
|Procedure: Blood Sampling|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Binding of 18F-TARP252 in brain |  | ongoing | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Transmembrane AMPA Receptor Regulatory Protein, Glutamate Receptors, Healthy Volunteers