NIMH DIRP Molecular Imaging Branch - Section on PET Imaging

Figure Legend: Magnetic resonance (MR) and MA1 parametric PET images of a 44-year old healthy male subject injected with 738 MBq of 11C-NOP-1A. Row A shows MR anatomic images and row B shows MA1 parametric images in axial (left), sagittal (middle), and coronal (right) views. Each pixel value represents distribution volume (VT) and is indicated in the VT color scale on right.

Background: Our laboratory developed 11C-NOP-1A, the first successful radioligand for the nociceptin/orphanin FQ peptide (NOP) receptor (Pike et al 2011; (PDF File) We found that 11C-NOP-1A is a useful radioligand for quantifying NOP receptors in monkey brain, and that its radiation dose is similar to that of other 11C-labeled ligands for neuroreceptors. We have recently extended this radioligand to healthy subjects and shown that it can quantify the regional distribution of NOP receptors in brain (Lohith et al., 2012; (PDF File)0.

The nociceptin/orphanin FQ peptide (NOP) receptor was cloned as an "orphan" receptor with no known endogenous transmitter. Subsequently, NOP itself was discovered as a 17 amino acid peptide with sequence similarities to endogenous opioid peptide dynorphin A. The NOP receptor is coupled to the G-protein Gi/Go, inhibits the production of cyclic adenosine monophosphate (cAMP), activates potassium channels, and inhibits calcium channels. Although the NOP receptor shares some amino acid sequence similarities with the classic opiate receptor, the mechanism of action of the NOP transmitter could not be blocked by the opioid antagonist naloxone; thus, the NOP receptor is considered a "non opiate" member of the opioid receptor family.

NOP receptors are widely distributed in brain, spinal cord, heart, lungs, kidneys, intestine, and immune cells of different mammalian species, where they mediate the actions of endogenous peptides in a complex manner. For example, animal studies suggest that NOP receptor activation in the periphery reduces pain perception, but similar activation in the brain increases pain perception. In addition, NOP receptors may mediate both the consumption of alcohol and anxiety-related behaviors. Elevated NOP receptor mRNA levels, as well as increased ³H-nociceptin binding in central amygdala, were both noted in Marchigian Sardinian alcohol-preferring (msP) rats. NOP receptor agonists were also shown to have anxiolytic effect across multiple species. As a result, investigators have focused on developing NOP receptor ligands for therapeutic trials in humans

Positron emission tomography (PET) radioligands would be very useful for exploring the roles that NOP receptors may play in human health and disease where relevant animal models showed changes. In addition, a NOP receptor radioligand could help determine the therapeutic mechanisms of some opiates; buprenorphine, for example, is used to treat both pain and heroin dependence, and may act on NOP as well as other opiate receptors. Finally, a PET radioligand for the NOP receptor would aid in the early evaluation of potential therapeutic NOP receptor agonists and antagonists. Such early studies could determine receptor occupancy and clarify required dose and dosing intervals, which are often critically important for the development of drugs that may have restricted access to brain because of the blood-brain barrier (BBB) and efflux transporters

References:

T.G. Lohith, S.S. Zoghbi, C.L. Morse, M.F. Araneta, V.N. Barth, N.A. Goebl, J.T. Tauscher, V.W. Pike, R.B. Innis, and M. Fujita. Brain and whole-body imaging of nociceptin/orphanin FQ peptide (NOP) receptors in humans using a novel PET ligand ¹¹C-NOP-1A. J. Nucl. Med, 53: 385-392, 2012. (PDF File)

V.W. Pike, K.S. Rash, Z. Chen, C. Pedregal, M.A. Statnick, Y. Kimura, J. Hong, S.S. Zoghbi, M. Fujita, S.L. Gackenheimer, J.A. Tauscher, V.N. Barth, and R.B. Innis. Synthesis and evaluation of radioligands for imaging brain NOP receptors with positron emission tomography. J. Med. Chem. 54: 2687-2700, 2011. (PDF File)