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

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 [(125)I]Tyr(0)-sauvagine and specific CRF1 antagonists CP154,526 and SN003 in human occipital cortex yielded maximal binding (Bmax) of 63.3 and 147.3 fmol/mg protein, respectively, and in human cerebellar cortex yielded Bmax 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, Bmax 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.

Figure 1.

Structures of radioligands. A) [¹¹C]R121920. B) [¹¹C]DMP696. C) [¹¹C]SN003.

Figure 2.

Unmetabolized parent fractions of the radioligands over time in baboon plasma. A) Fraction of [¹¹C]R121920. B) Fraction of [¹¹C]DMP696. Filled circles represent mean fractions in six determinations and error bars represent standard deviations.

Figure 3.

Time‐activity curves of the radioactivity in selected regions of interest in baboon brain during PET imaging. A) Time‐activity curve of [¹¹C]R121920. B) Time‐activity curve of [¹¹C]DMP696.

Figure 4.

Representative volume of distribution (V_T) voxel maps of C‐11 CRF1 radioligands in the same baboon from 120 min emission scans performed under isoflurane anesthesia. Intensity bar shows corresponding V_T values for each intensity level. A) Cropped saggital, coronal, and axial magnetic resonance imaging (MRI) images of baboon. B) V_T voxel map of [¹¹C]R121920 (injected dose [ID], 4.1 mCi; specific activity [SA], 1.8 Ci/micromole). C) V_T voxel map of [¹¹C]DMP696 (ID, 4.0 mCi; SA, 2.2 Ci/micromole). D) V_T voxel map of previously reported CRF1 radioligand [¹¹C]SN003 (ID, 4.7 mCi; SA, 2.1 Ci/micromole).

Figure 5.

Representative autoradiography images of [¹²⁵I]Tyr⁰‐sauvagine binding to selected regions of human and baboon brain. A) Total binding in human occipital cortex (OC). B) Total binding in human cerebellum (CER). C) Total binding in baboon cerebellum. D) Nonspecific (NS) binding in human OC with CP154,526 as displacer. E) NS binding in human CER with CP154,526 as displacer. F) NS binding in baboon CER with CP154,526 as displacer. G) NS binding in human OC with SN003 as displacer. H) NS binding in human CER with SN003 as displacer. I) NS binding in baboon CER with SN003 as displacer.