PET Imaging of CRF1 with [11C]R121920 and [11C]DMP696: is the target of sufficient density?

Sullivan, Gregory M.; Parsey, Ramin V.; Kumar, J.S. Dileep; Arango, Victoria; Kassir, Suham A.; Huang, Yung-yu; Simpson, Norman R.; Van Heertum, Ronald L.; Mann, J. John

doi:10.1016/j.nucmedbio.2007.01.012

« Previous Next »Nuclear Medicine and Biology
Volume 34, Issue 4 , Pages 353-361, May 2007

PET Imaging of CRF1 with [¹¹C]R121920 and [¹¹C]DMP696: is the target of sufficient density?

Gregory M. Sullivan
- Division of Neuroscience, Department of Psychiatry, New York State Psychiatric Institute, Columbia University, New York, NY 10032, USA
- Corresponding author. Division of Neuroscience, Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA. Tel.: +1 212 543 6760; fax: +1 212 543 5437.
Ramin V. Parsey
- Division of Neuroscience, Department of Psychiatry, New York State Psychiatric Institute, Columbia University, New York, NY 10032, USA
J.S. Dileep Kumar
- Division of Neuroscience, Department of Psychiatry, New York State Psychiatric Institute, Columbia University, New York, NY 10032, USA
Victoria Arango
- Division of Neuroscience, Department of Psychiatry, New York State Psychiatric Institute, Columbia University, New York, NY 10032, USA
Suham A. Kassir
- Division of Neuroscience, Department of Psychiatry, New York State Psychiatric Institute, Columbia University, New York, NY 10032, USA
Yung-yu Huang
- Division of Neuroscience, Department of Psychiatry, New York State Psychiatric Institute, Columbia University, New York, NY 10032, USA
Norman R. Simpson
- Division of Neuroscience, Department of Psychiatry, New York State Psychiatric Institute, Columbia University, New York, NY 10032, USA
Ronald L. Van Heertum
- Department of Radiology, Columbia University, New York, NY 10032, USA
J. John Mann
- Division of Neuroscience, Department of Psychiatry, New York State Psychiatric Institute, Columbia University, New York, NY 10032, USA
- Department of Radiology, Columbia University, New York, NY 10032, USA

Received 4 December 2006; received in revised form 29 January 2007; accepted 29 January 2007. published online 02 April 2007.

Abstract

Aim

Overstimulation of the CRF type 1 receptor (CRF1) is implicated in anxiety and depressive disorders. The aim of this study was to investigate the in vivo binding characteristics of [¹¹C]R121920 and [¹¹C]DMP696 in the nonhuman primate for application in positron emission tomography (PET) studies of CRF1.

Methods

PET imaging with the two novel CRF1 radioligands was performed in baboon. In vitro binding studies for CRF1 were performed in postmortem brain tissue of baboon and human to assess sufficiency of receptor density for PET.

Results

Both [¹¹C]R121920 and [¹¹C]DMP696 distributed rapidly and uniformly throughout the brain. Washout was comparable across brain regions, without differences in volume of distribution between regions reported to have high and low in vitro CRF1 binding. Membrane-enriched tissue homogenate assay using [¹²⁵I]Tyr⁰-sauvagine and specific CRF1 antagonists CP154,526 and SN003 in human occipital cortex yielded maximal binding (B_max) of 63.3 and 147.3 fmol/mg protein, respectively, and in human cerebellar cortex yielded B_max of 103.6 and 64.6 fmol/mg protein, respectively. Dissociation constants (K_D) were subnanomolar. In baboon, specific binding was not detectable in the same regions; therefore, B_max and K_D were not measurable. Autoradiographic results were consistent except there was also detectable CRF1-specific binding in baboon cerebellum.

Conclusion

Neither [¹¹C]R121920 nor [¹¹C]DMP696 demonstrated quantifiable regional binding in vivo in baboon. In vitro results suggest CRF1 density in baboon may be insufficient for PET. Studies in man may generate more promising results due to the higher CRF1 density compared with baboon in cerebral cortex and cerebellum.

Keywords: Corticotropin-releasing factor (CRF), Positron emission tomography (PET), R121220, DMP696, SN003, Baboon, Radioligand