PET Whole Body Imaging Using a Peripheral Benzodiazepine Receptor Ligand [C-11]PBR28

The peripheral benzodiazepine receptor (PBR) is distinct from central benzodiazepine
receptors associated with GABA(A) receptors. Although PBR was initially identified in
peripheral organs such as kidneys, endocrine glands and lungs, later studies identified PBR
in the central nervous system. In normal conditions, PBR is expressed in low levels in some
neurons and glial cells. PBR can be a clinically useful marker to detect neuroinflammation
because activated microglial cells in inflammatory areas express much greater levels of PBR
than in microglial cells in resting conditions.

PBR has been imaged with positron emission tomography (PET) using
[(11)C]1-(2-chlorophenyl-N-methylpropyl)-3-isoquinoline carboxamide (PK11195). However, this
classical ligand provides only low levels of specific signals and is not sensitive to detect
changes that occurred in vivo. Recently we developed a new ligand,
N-acetyl-N-(2-[(11)C]methoxybenzyl)-2-phenoxy-5-pyridinamine [(11)C]PBR28), which showed much
greater specific signals than [(11)C]PK11195 in non-human primates. Therefore, [(11)C]PBR28
is a promising PET ligand. However, radiation absorbed doses have not been estimated from
human whole body imaging.

The initial purpose of this protocol is to estimate radiation absorbed doses of [11C]PBR28 by
performing whole body imaging studies on ten healthy human subjects. The radiation absorbed
doses are required to apply this PET ligand in various neurological and psychiatric disorders
in the future.

Under the current and other protocols using [(11)C]PBR28, we found that some healthy subjects
and patients have very low to no binding of [(11)C]PBR28. We studied approximately 188
subjects in total under protocols using [11C]PBR28 and found that 8.5% (16/188) had almost no
binding of [(11)C]PBR28. Several published ligands have been tested and all of the tested
ligands recently developed show low affinity to a subset of humans. By using [(11)C]PBR28, we
need to exclude PBR28 nonbinders from the data to study changes in PBR. By using a PET ligand
that binds equally to PBR28 binders and nonbinders, we would be able to study all subjects.
We also confirmed that PBR28 nonbinders determined by PET do not show binding in in vitro
binding assays using blood cells.

We wish to test new ligands currently being developed in our chemistry group by obtaining
blood samples from additional PBR28 nonbinders (= low affinity binders) and by performing in
vitro binding assays. Because our preliminary analysis of whole body imaging has shown that
the differences between PBR28 binders and nonbinders might somewhat vary among organs and the
cause of the nonbinding phenomenon is not fully understood, after identifying PBR28
nonbinders by binding assays, we will perform whole body imaging using [(11)C]PBR28.

- INCLUSION CRITERIA:

All subjects must be healthy and aged 18-65 years.

EXCLUSION CRITERIA:

- Current psychiatric disease, substance abuse or severe systemic disease based on
history and physical exam.

- Laboratory tests with clinically significant abnormalities.

- Prior participation in other research protocols or clinical care in the last year such
that radiation exposure including that from this protocol would exceed the guidelines
set by the Radiation Safety Committee (RSC).

- Pregnancy and breast feeding.

- Positive HIV test.

- Cannot lie flat for 2 - 3 h.