Positron Emission Tomography (PET) Imaging of Opioid Receptors

Abstract

The opioid system consists of opioid receptors (which mediate the actions of opium), their endogenous ligands (the enkephalins, endorphins, endomorphins, dynorphin, and nociceptin), and the proteins involved in opioid production, transport, and degradation. PET tracers for the various opioid receptor subtypes are available, and changes in regional opioidergic activity have been assessed during both sensory and affective processing in healthy individuals and in various disease conditions such as chronic pain, neurodegeneration, epilepsy, eating disorders, behavioral addiction, and substance abuse. It is not always clear whether observed changes of tracer binding reflect altered release of endogenous opioids or altered opioid receptor expression. This issue may be resolved by studies in experimental animals that combine in vivo PET imaging with ex vivo immunohistochemistry. Some radioligands for opioid receptors have suboptimal kinetics (i.e., slow dissociation from their target protein) or can induce undesired side effects even at low administered doses (sedation, respiratory arrest). Yet, PET offers the unique opportunity of quantifying opioid receptor-mediated signaling in the living human brain. PET imaging has provided evidence for a link between opioid neurotransmission and peripheral immune activation.

Synthesis and opioid receptor binding of indium (III) and [111In]-labeled macrocyclic conjugates of diprenorphine: novel ligands designed for imaging studies of peripheral opioid receptors

“…Since radiolabeled analogs of DPN having fluoroalkyl and iodoallyl groups at the C6-oxygen (Fig. 1) maintain high opioid receptor binding affinity, 1–4,16 we chose to investigate conjugation of DOTA at this position. Support also comes from the high binding affinity observed for some bivalent opioid receptor ligands, developed to detect homomeric and heteromeric receptors, which are joined by long linkers through the C6-positions of oxymorphone or naltrexone.…”

“…1–4 Despite thirty years of progress in brain imaging, few advances have been made in the development of radioligands optimized for imaging studies of the important functional roles played by the peripheral opioid receptors. These include mediation of cardiovascular functions, 5 visceral and inflammatory pain relief, 6 cell death and survival, 7 and smooth muscle contraction.…”

“…1–4 DPN congeners labeled with iodine-123 have also been developed for brain imaging by SPECT (Fig. 1).…”

Diels–Alder Adducts of Morphinan-6,8-Dienes and Their Transformations

“…The same products were formed in boiling THF (6.5 h), with respective yields of 20% ( 287) and 74% benzazocine (288). The authors [45] assumed that the rearrangement of the stannylated Diels-Alder adduct (287) to the destannylated N 17 -Boc-benzazocine derivative (288) was achieved via the stannylated N 17 -Boc-benzazocine compound (290). The reaction of 9f with trifluoroacetylacetylene readily (THF, 5-20 • C, for a few minutes) gave the normal Diels-Alder adduct (289, isolated yield: 47%) and the rearranged adduct (288) in a ratio of 11:3 (determined by 19 F-NMR).…”

Optimized image acquisition for dopamine transporter imaging with ultra-high resolution clinical pinhole SPECT

“…Mediso X-Ring/4R), or a large number of focusing collimators and detectors (e.g. NeuroFocus and inSpira HD with a resolution of about 7 mm (Van De Giessen and Booij 2010, Stoddart and Stoddart 1992, Sensakovic et al 2013), yet only few clinical validations with these scanners are available (Van De Giessen and Booij 2010, Tavares et al 2013, Dierckx et al 2014 and some are not even manufactured anymore. A SPECT system which could achieve a much better resolution-sensitivity tradeoff would be very desirable for its ease of dose requirement and possibility for dynamic scans or longitudinal studies.…”