An Exploratory Study of 18F-Labeled Hydroxyphenethylguanidines in Heart Failure Patients

The human heart contains many nerve fibers that are involved in controlling the heart's
pumping function. Several heart diseases have been shown to damage the nerves in the heart.
Studies have shown that damage to the heart nerves may be a cause of death in patients with
diseases like heart failure or diabetes.

Two new radioactive drugs been developed at the University of Michigan for taking pictures
of the nerve fibers in the heart using a medical imaging method called positron emission
tomography (PET).

These two drugs are 4-[18F]fluoro-meta-hydroxyphenethylguanidine ([18F]4F-MHPG) and
3-[18F]fluoro-para-hydroxyphenethylguanidine ([18F]3F-PHPG). Initial PET imaging studies in
normal human subjects (see NCT 02385877) have shown that [18F]4F-MHPG and [18F]3F-PHPG are
each able to provide a detailed regional map of the distribution of nerve fibers in the
heart.

In Stage 1 of this study, enrolled subjects with heart failure will undergo PET studies with
[18F]4F-MHPG and [18F]3F-PHPG to allow direct comparison of the imaging properties,
metabolism and pharmacokinetics of the two radioactive drugs in the same subjects.

A third PET scan with [13N]ammonia will be done to assess resting blood flow in different
areas of the heart. The results of these studies will be used to select the better of the
two tracers for further study in patients with heart disease.

In Stage 2 of the study, enrolled subjects with heart failure will undergo additional PET
evaluations of the imaging properties and kinetics of the cardiac nerve tracer selected in
Stage 1 (either [18F]4F-MHPG or [18F]3F-PHPG).

Again, a PET scan with [13N]ammonia will also be performed to measure regional resting blood
flow. A third PET scan with [11C]meta-hydroxyephedrine ([11C]HED), an established cardiac
nerve tracer, will also be done to address research questions related to the mechanisms
involved in the retention of [18F]4F-MHPG and [18F]3F-PHPG inside the nerve of the heart.

For all study stages, subjects will be assessed during the scan for heart rate, blood
pressure and oxygen saturation. Patients will be followed at 30 min, 24 hours and 30 hours
regarding any adverse events or serious adverse events they might have experienced. These
will be reported as required.

Inclusion Criteria:

- Age 18-80y

- Cardiomyopathy (ischemic and non-ischemic)

- Left ventricular ejection fraction (LVEF) < 35%

- Clinically appropriate referral for surgical implantation of an implantable
cardiodefibrillator (ICD) for primary prevention of sudden cardiac death

- Not claustrophobic

- Ability to lie flat for 90 min

- Give informed consent

Exclusion Criteria:

- Revascularization such as the placement of a stent or balloon angioplast in the
preceding 40 days

- Renal dysfunction with eGFR < 50 mL/min/1.73 m2

- Currently taking medications or drugs that may alter PET scans of cardiac sympathetic
nerve terminals with these tracers, including any of the following:

- Tricyclic antidepressants, which inhibit the norepinephrine transporter, such as
amitriptyline, desipramine, imipramine, etc.

- Cold medications (e.g., Sudafed®, as they may contain sympathomimetic amines,
such as phenylephrine, phenylpropanolamine, pseudoephedrine, etc.)

- Nasal decongestants (some use phenylephrine as the active agent)

- Cocaine (which inhibits the norepinephrine transporter)

- Tetrabenazine (Xenazine, which inhibits VMAT2 transporters on vesicles inside
neurons)

- Monoamine oxidase inhibitors (MAOI)

- Some antihypertensive drugs (reserpine, labetalol, α-methyldopa, and clonidine)

- Pregnancy or lactation

- Claustrophobia

- Inability to lie flat for 90 min