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Physician-Sponsored IND Application: Evaluation of R-[11C]rolipram
EVALUATION OF (R)-[11C]ROLIPRAM AS A PET TRACER TO IMAGE
PHOSPHODIESTERASE 4 IN BRAIN
CONTENTS
Form FDA 1571, Investigational New Drug Applications
i
Form FDA 1572, Statement of Investigator
ii
I.
Introductory Statement of Purpose and General Plan
II.
Study Protocol: PET Whole Body Biodistribution and Test Retest Brain Imaging Studies
Using a Phosphodiesterase 4 Inhibitor (R)-[11C]Rolipram
A. Precis
III. Chemistry, Manufacture and Control
IV. Pharmacology and Toxicology
V. Animal Experimentation
VI. Human Experience
VII. Environmental Assessment
VIII. Case Report Form
IX. References
X. APPENDICES
A. Investigator data
B. Complete Study Protocol
C. IRB Protocol Approval
D. Dr. Martin's letter summarizing the information on Pharmacology and Toxicology
E. Case Report Form
NOTE: Pages in the Appendices are numbered A1, A2, A3 etc; then B1, B2, B3, etc.
Chemistry, Manufacturing, and Controls
Document No.
Section
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CMC
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Master Batch Record
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QC Form
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Radiopharmacy Form
5
SOP: Standard Operating Procedures
6
Annual Testing for Radionuclidic Identity
7
Certificate of Analysis for starting Materials
8
(R)-Rolipram Standard SolutionP
9
Validation Runs
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Physician-Sponsored IND Application: Evaluation of R-[11C]rolipram
EVALUATION OF (R)-[11C]ROLIPRAM AS A PET TRACER TO IMAGE
PHOSPHODIESTERASE 4 IN BRAIN
I.
Introductory Statement of Purpose and General Plan
cAMP is a prevalent second messenger that mediates signal transduction of several neurotransmitters including dopamine, epinephrine, histamine, and adenosine. cAMP is synthesized
from ATP by adenylyl cyclase and metabolized by PDEs. Thus, PDEs terminate the actions of
the second messenger cAMP. At least 11 types of PDE exist in mammals, and PDE4 is selective
to cAMP in the brain. PDE4 consists of four independently coded subtypes, PDE4A, B, C, and D
(Houslay 2001).
There is large body of literature indicating that the cAMP pathway plays important roles in
psychiatric illnesses, including mood disorders (Duman et al 1997) and drug addiction (Nestler
and Aghajanian 1997). Among components of the cAMP pathway, PDE4 appears to be critical
for antidepressant effects. Repeated antidepressant treatment increased PDE4 (Takahashi et al
1999; Ye et al 1997; Zhao et al 2003), and an inhibitor of PDE4, rolipram, showed antidepressant
effects both in animals (Mizokawa et al 1988; Wachtel 1983) and humans (Fleischhacker et al
1992). However, adverse reactions such as emesis and sedation precluded rolipram from clinical
applications. Rolipram is almost equipotent at all four PDE4 subtypes. Inhibitors selective to
PDE subtypes may have therapeutic effects with minimal adverse reactions (O'Donnell and
Zhang 2004).
Rolipram has two enantiomers. The R(-) enantiomer has 20 times greater affinity than the
S(+) enantiomer and the racemic rolipram had Kd = 1–2 nM (Schneider et al 1986). In the brain,
the density of the racemic rolipram binding sites is high (20 nM) (Schneider et al 1986) compared to other proteins that have been imaged in vivo, and the lipophilicity of rolipram appears to
be appropriate for brain imaging (Waterhouse 2003). Considering the importance of PDE4 in
diseases, high density of PDE4, and chemical characteristics of (R)-rolipram, this compound may
be a quite promising as a brain imaging agent. In fact, following initial rodent studies (Lourenco
et al 1999; Lourenco et al 2001b), (R)-[11C]rolipram has been successfully applied in non-human
primates (Tsukada et al 2001) and humans (DaSilva et al 2002; Matthews et al 2003). PDE4 is
activated by phosphorylation with protein kinase A (Conti et al 1995), and a study using recombinant DNAs has indicated that phosphorylation of PDE4 affects binding affinity of rolipram
(Hoffmann et al 1998). Therefore, in addition to measuring binding density and affinity, (R)[11C]rolipram PET imaging may provide information on the phosphorylation state of PDE4.
Radiation absorbed doses of (R)-[11C]rolipram has been estimated from rat but not from human data (Lourenco et al 2001b). The whole body absorbed dose was 0.0052 rad/mCi, which is
well within the limit. Prior studies of (R)-[11C]rolipram in humans and non-human primates were
not quantitative and did not distinguish changes in delivery of radioligand from changes in density of PDE4. Using a small animal PET scanner, Advanced Technology Laboratory Animal Scanner (ATLAS) (Seidel et al 2003), we have established a method to accurately measure PDE4 levels in living rats (Fujita et al 2004). In the present protocol, we plan to perform a kinetic whole
body imaging study in 10 healthy humans in order to estimate radiation-absorbed doses of (R)[11C]rolipram. By doing this, we will confirm that radiation-absorbed doses of (R)-[11C]rolipram
is within limits, and is a safe radioligand for human use. Then we will establish an accurate
method to measure PDE4 levels by performing test retest brain imaging studies and comparing
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Physician-Sponsored IND Application: Evaluation of R-[11C]rolipram
results in two studies in individual subjects. Both of these studies will be performed with an intravenous injection of up to 20 mCi of (R)-[11C]rolipram and imaging for 2 h.
Roland Martin, MD, of Neuroimmunology Branch, NINDS, NIH, has IND#60,932 for the use of
rolipram. He has authorized me to cite information from this application. Dr. Martin sent a letter to the the FDA for his IND that allows us to cite the information. For a summary of the information on “Pharmacology and Toxicology”, “animal Experimentation” and “Previous Human
Experience”, please refer to Dr. Martin’s letter to the FDA dated December 26, 2000, which we
include as Appendix D. Therefore, the major components of the current application are the study
protocol and “Chemistry, Manufacturing, and Controls.”
Please note that Dr. Martin’s IND and other studies have safely used 1.5 – 3.0 mg daily dose in
human. For the current study, the injected mass dose will be less than 10 ug.
II.
Study Protocol: PET Whole Body Biodistribution and Test Retest Brain Imaging
Studies Using a Phosphodiesterase 4 Inhibitor (R)-[11C]Rolipram
A. Precis
The complete protocol is located in Appendix B. A brief summary is included below.
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. A subsequent study on healthy human
subjects showed good brain uptake and good image 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.
III. Chemistry, Manufacture and Control
The CMC Section is a separate portion of this application.
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Physician-Sponsored IND Application: Evaluation of R-[11C]rolipram
IV.
Pharmacology and Toxicology
See Dr. Martin's IND and Appendix E for this information.
V.
Animal Experimentation
See Dr. Martin's IND and Appendix E for information on nonradioactive rolipram.
The dosimetry on R-[11C]rolipram was reported based on rodent biodistribution studies
(Lourenco et al 2001a). Typical of short-lived 11C-containing radiotracers, the radiation exposure
was relatively low – e.g., whole body dose of 5.2 mrem/mCi. The proposed protocol will obtain
biodistribution data in human subjects for more accurate estimation of radiation dose.
VI.
Human Experience
See Dr. Martin's IND and Appendix E for this information.
VII.
Environmental Assessment
A categorical exclusion is requested regarding the environmental assessment. Activity excreted by the subjects is disposed through the sewage system at such low amounts that there will
be no detrimental effects to the environment.
All potentially contaminated laboratory materials are held at least 10 half lives for decay. In
addition, these materials are surveyed to ensure background levels of activity prior to disposal
through regular waste systems.
VIII. Case Report Form
The CRF is in Appendix E.
IX.
References
Conti, M., Nemoz, G., Sette, C., Vicini, E., 1995. Recent progress in understanding the hormonal
regulation of phosphodiesterases. Endocr Rev 16:370-389.
DaSilva, J. N., Lourenco, C. M., Meyer, J. H., Hussey, D., Potter, W. Z., Houle, S., 2002. Imaging cAMP-specific phosphodiesterase-4 in human brain with R-[11C]rolipram and positron emission tomography. Eur J Nucl Med Mol Imaging 29:1680-1683.
Duman, R. S., Heninger, G. R., Nestler, E. J., 1997. A molecular and cellular theory of depression. Arch Gen Psychiatry 54:597-606.
Fleischhacker, W. W., Hinterhuber, H., Bauer, H., Pflug, B., Berner, P., Simhandl, C., Wolf, R.,
Gerlach, W., Jaklitsch, H., Sastre-y-Hernandez, M., Schmeding-Wiegel, H., SpernerUnterweger, B., Voet, B., Schubert, H., 1992. A multicenter double-blind study of three
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Physician-Sponsored IND Application: Evaluation of R-[11C]rolipram
different doses of the new cAMP-phosphodiesterase inhibitor rolipram in patients with
major depressive disorder. Neuropsychobiol 26:59-64.
Fujita, M., Zoghbi, S., Crescenzo, M., Hong, J., Musachio, J., Lu, J. Q., Liow, J. S., Seneca, N.,
Tipre, D., Cropley, V., Gee, A., Seidel, J., Green, M., Pike, V., Innis, R. B., 2004. PET
imaging of brain phosphodiesterase 4 in rats using [C-11]rolipram. NeuroImage 12:T72.
Hoffmann, R., Wilkinson, I. R., McCallum, J. F., Engels, P., Houslay, M. D., 1998. cAMPspecific phosphodiesterase HSPDE4D3 mutants which mimic activation and changes in
rolipram inhibition triggered by protein kinase A phosphorylation of Ser-54: generation
of a molecular model. Biochem J 333:139-149.
Houslay, M. D., 2001. PDE4 cAMP-specific phosphodiesterases. Prog Nucleic Acid Res Mol
Biol 69:249-315.
Lourenco, C. M., DaSilva, J. N., Warsh, J. J., Wilson, A. A., Houle, S., 1999. Imaging of cAMPspecific phosphodiesterase-IV: comparison of [11C]rolipram and [11C]Ro 20-1724 in rats.
Synapse 31:41-50.
Lourenco, C. M., Houle, S., Wilson, A. A., DaSilva, J. N., 2001. Characterization of R[11C]rolipram for PET imaging of phosphodieterase-4: in vito binding, metabolism, and
dosimetry studies in rats. Nucl Med Biol 28:347-358.
Matthews, J. C., Passchier, J., Wishart, M. O., Martarello, L., Comley, R. A., C.A., P., Knibb, S.
T., Hopper, R. V., J., B., Gee, A. D., 2003. The characterisation of both the R and S enantiomers of [11C]rolipram in man. J Cereb Blood Flow Metab 23:678.
Mizokawa, T., Kimura, K., Ikoma, Y., Hara, K., Oshino, N., Yamamoto, T., Ueki, S., Wachtel,
H., 1988. The effect of a selective phosphodiesterase inhibitor, rolipram, on muricide in
olfactory bulbectomized rats: Potential antidepressant activity of rolipram and other selective cyclic adenosine 3',5'-monophosphate phosphodiesterase inhibitors. Jpn J Pharmacol
48:357-364.
Nestler, E. J., Aghajanian, G. K., 1997. Molecular and cellular basis of addiction. Science
278:58-63.
O'Donnell, J. M., Zhang, H. T., 2004. Antidepressant effects of inhibitors of cAMP phosphodiesterase (PDE4). Trends Pharmacol Sci 25:158-163.
Schneider, H. H., Schmiechen, R., Brezinski, M., Seidler, J., 1986. Stereospecific binding of the
antidepressant rolipram to brain protein structures. Eur J Pharmacol 127:105-115.
Seidel, J., Vaquero, J. J., Green, M. V., 2003. Resolution uniformity and sensitivity of the NIH
ATLAS small animal PET scanner: comparison to simulated LSO scanners without
depth-of-interaction capability. IEEE Trans Nucl Sci 50:
Takahashi, M., Terwilliger, R., Lane, C., Mezes, P. S., Conti, M., Duman, R. S., 1999. Chronic
antidepressant administration increases the expression of cAMP-specific phosphodiesterase 4A and 4B isoforms. J Neurosci 19:610-618.
Tsukada, H., Harada, N., Ohba, H., Nishiyama, S., Kakiuchi, T., 2001. Facilitation of dopaminergic neural transmission does not affect [11C]SCH23390 binding to the striatal D1 dopamine receptors, but the facilitation enhances phosphodiesterase type-IV activity through
D1 receptors: PET studies in the conscious monkey brain. Synapse 42:258-265.
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Physician-Sponsored IND Application: Evaluation of R-[11C]rolipram
Wachtel, H., 1983. Potential antidepressant activity of rolipram and other selective cyclic adenosine 3',5'-monophosphate phosphodiesterase inhibitors. Neuropharmacology 22:267-272.
Waterhouse, R. N., 2003. Determination of lipophilicity and its use as a predictor of blood-brain
barrier penetration of molecular imaging agents. Mol Imaging Biol 5:376-389.
Ye, Y., Conti, M., Houslay, M. D., Farooqui, S. M., Chen, M., O'Donnell, J. M., 1997. Noradrenergic activity differentially regulates the expression of rolipram-sensitive, highaffinity cyclic AMP phosphodiesterase (PDE4) in rat brain. J Neurochem 69:2397-2404.
Zhao, Y., Zhang, H. T., O'Donnell, J. M., 2003. Antidepressant-induced increase in high-affinity
rolipram binding sites in rat brain: dependence on noradrenergic and serotonergic function. J Pharmacol Exp Ther 307:246-253.
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X.
APPENDICES
A. Investigator data
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Physician-Sponsored IND Application: Evaluation of R-[11C]rolipram
APPENDIX
B. Complete Study Protocol
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Physician-Sponsored IND Application: Evaluation of R-[11C]rolipram
APPENDIX
C. IRB Protocol Approval
The NIMH IRB reviewed this protocol on March 23, 2004. See attached minutes of meeting.
We made all the requested modifications. It will be finally approved after we have approval of
this IND from the FDA.
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Physician-Sponsored IND Application: Evaluation of R-[11C]rolipram
APPENDIX
D. Dr. Martin's letter summarizing the information on Pharmacology and Toxicology
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Physician-Sponsored IND Application: Evaluation of R-[11C]rolipram
APPENDIX
E. Case Report Form
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