PET Whole Body Biodistribution and Test Retest Bain Imaging Studies Using a Phosphodiesterase 4 Inhibitor (R)-[11C]Rolipram

Both basic and clinical studies have indicated that the 3', 5'-cyclic adenosine monophosphate
(cAMP) system plays critical roles in several brain diseases, particularly in mood disorders
and drug addiction. cAMP is synthesized from adenosine 5'-triphosphate (ATP) by adenylyl
cyclase and metabolized by cyclic nucleotide phosphodiesterases (PDEs). Among components of
the cAMP pathway, PDE4 appears to be critical for antidepressant effects.
4-[3-(cyclopentoxyl)-4-methoxyphenyl]-2-pyrrolidone (rolipram) is an inhibitor of PDE4. As a
positron emission tomography (PET) brain imaging agent, rolipram has good properties such as
high affinity of 1-2 nM and appropriate lipophilicity (Log P) of ~3. A rat study gave an
estimation of low radiation absorbed doses of the active enantiomer (R)-[11C]rolipram.
ciociWEge quality. Therefore, R-[11C]rolipram is a promising PET ligand. However, radiation
absorbed doses have not been estimated from human whole body imaging studies and a method to
measure binding of (R)-[11C]rolipram in human brain has not been established.



The purposes of this protocol are to estimate radiation absorbed doses of (R)-[11C]rolipram
by performing whole body imaging studies on healthy human subjects and also to establish an
accurate method to measure PDE4 levels in brain by performing test retest brain imaging
studies. The results of this overall study are required to apply this PET ligand in various
neurological and psychiatric disorders in the future.

- INCLUSION CRITERIA:

All subjects must be healthy and aged 18 65 years.

EXCLUSION CRITERIA:

PART 1 (WHOLE BODY IMAGING STUDIES):

1. Current psychiatric disease, substance abuse or severe systemic disease based on
history and physical exam, poor vision or hearing.

2. Laboratory tests with clinically significant abnormalities.

3. Prior participation in other research protocols or clinical care in the last year such
that radiation exposure including that from this protocol would exceed a half of the
annual limits. Because human dosimetry of (R)-[(11)C]rolipram has been estimated using
rhesus monkeys, the total exposure including that from the (R)-[(11)C]rolipram whole
body imaging study will be limited to a half of the RSC guidelines.

4. Pregnancy and breast feeding.

5. Positive HIV test.

6. Positive urine drug screen.

PART 2 (TEST RETEST BRAIN IMAGING STUDIES):

1. Current psychiatric disease, substance abuse or severe systemic disease based on
history and physical exam, poor vision or hearing.

2. Laboratory tests with clinically significant abnormalities.

3. Prior participation in other research protocols or clinical care in the last year such
that radiation exposure would exceed the annual limits. Results of part 1 will be used
to calculate total radiation exposure within a year.

4. Pregnancy and breast feeding.

5. Claustrophobia.

6. Presence of ferromagnetic metal in the body or heart pacemaker.

7. Positive HIV test.

8. A history of brain disease.