Clinical Translation of 18F-Labeled Hydroxyphenethylguanidines

Study Overview
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Brief Summary
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The purpose of this study is to perform first-in-human PET imaging studies of two new cardiac sympathetic nerve imaging agents, 4-[18F]fluoro-meta-hydroxyphenethylguanidine ([18F]4F-MHPG) and 3-[18F]fluoro-para-hydroxyphenethylguanidine ([18F]3F-PHPG).

Detailed Description
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In this study, PET imaging studies of two structurally related 18F-hydroxyphenethylguanidines, 4-[18F]fluoro-meta-hydroxyphenethylguanidine ([18F]4F-MHPG) and 3-[18F]fluoro-para-hydroxyphenethylguanidine ([18F]3F-PHPG) will be performed. All studies will be performed in normal healthy volunteers. PET stands for Positron Emission Tomography which is a type of imaging that uses a radioactive tracer. This is also called a radiotracer which is a compound linked to a radioactive element. Most compounds are short-lived, meaning that the radioactivity breaks down quickly or is excreted from the body. In the first stage of the study, dynamic PET imaging for 90 min will be done with [18F]4F-MHPG (n = 4) and [18F]3F-PHPG (n = 4). Data from these studies will assess each radiotracer's imaging properties, pharmacokinetics and metabolic breakdown in plasma. Application of tracer kinetic analysis methods to the kinetics of each tracer in heart and plasma will be studied to see if these methods can provide accurate measurements of regional nerve sympathetic nerve density in the hearts of human subjects. Results from these initial studies will be used to select the lead compound for further studies in patient populations. In the second stage of the study, whole-body PET imaging studies (n = 4) with the selected lead radiotracer will be performed to acquire data necessary for generating more accurate human radiation absorbed dose estimates.

Official Title
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Clinical Translation of 18F-Labeled Hydroxyphenethylguanidines for Quantification of Regional Cardiac Sympathetic Nerve Density With PET

Conditions
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Autonomic Peripheral Nervous System Diseases

Intervention / Treatment
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* Drug: [18F]4F-MHPG
* Drug: [18F]3F-PHPG


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Non-obese (BMI < 30) Normal blood pressure Normal blood lipid profile No history of prior cardiovascular disease Not susceptible to claustrophobia Ability to lay flat for 90 min Exclusion Criteria: Obesity (BMI > 30) Risk factors for heart disease (age > 55y, hypertension, smoking, high blood pressure, high cholesterol levels, diabetes, etc.) History of heart disease (heart attack, atrial fibrillation, ventricular tachycardia, exertional angina) Currently using certain medications that may interact with cardiac nerves (antidepressants, cold medications, nasal decongestants, monoamine oxidase inhibitors, etc.) Claustrophobia Inability to lie flat for 90 min Pregnant or breast feeding

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

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Protocol 1: [18F]4F-MHPG<br>Subjects (n = 4) will be injected one time with 6.5 mCi of 4-[18F]fluoro-meta-hydroxyphenethylguanidine ([18F]4F-MHPG) and receive a 90 minute PET scan. | Drug: [18F]4F-MHPG<br>* IV injection of [18F]4F-MHPG<br>* Other names: 4-[18F]fluoro-meta-hydroxyphenethylguanidine;|
| Experimental: Protocol 1: [18F]3F-PHPG<br>Subjects (n = 4) will be injected one time with 6.5 mCi of 3-[18F]fluoro-para-hydroxyphenethylguanidine ([18F]3F-PHPG) and receive a 90 minute PET scan. | Drug: [18F]3F-PHPG<br>* IV injection of [18F]3F-PHPG<br>* Other names: 3-[18F]fluoro-para-hydroxyphenethylguanidine;|
| Experimental: Protocol 2: Biodistribution Studies<br>Subjects (n = 4) will be injected one time with 6.5 mCi of either [18F]4F-MHPG or [18F]3F-PHPG (whichever is selected based on Protocol 1 studies) and receive four whole-body PET scans, starting at 5 min, 60 min, 150 min and 360 min after tracer injection. | Drug: [18F]4F-MHPG<br>* IV injection of [18F]4F-MHPG<br>* Other names: 4-[18F]fluoro-meta-hydroxyphenethylguanidine;Drug: [18F]3F-PHPG<br>* IV injection of [18F]3F-PHPG<br>* Other names: 3-[18F]fluoro-para-hydroxyphenethylguanidine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite measure based on radiotracer tissue uptake ratios (heart-to-lung ratio, heart-to-liver ratio, heart-to-blood ratio) and rates of metabolism in plasma (half-time, in minutes) of [18F]4F-MHPG and [18F]3F-PHPG in healthy subjects. | These data will be used to select the lead radiotracer for further clinical development. | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Radiation Dose | Human radiation absorbed dose estimates based on the kinetics of the selected lead radiotracer in various organs, as extracted from whole-body PET scans. | 1 year | 
| Number of Adverse Events | Number of study participants with adverse events as a measure of safety and tolerability following intravenous administration of [18F]4F-MHPG or [18F]3F-PHPG | 30 days |