Molecules Active Key a Diary

molecules Review A Survey of Molecular Imaging of Opioid Receptors Paul Cumming 1,2,* ,János Marton 3, Tuomas O. Lilius 4 , Dag Erlend Olberg 5 and Axel Rominger 1,* 1 Department of Nuclear Medicine, University of Bern, Inselspital, Freiburgstraße 18, 3010 Bern, Switzerland 2 School of Psychology and Counselling and IHBI, Queensland University of Technology, QLD 4059, Brisbane, Australia 3 ABX Advanced Biochemical Compounds, Biomedizinische Forschungsreagenzien GmbH, Heinrich-Glaeser-Strasse 10-14, D-1454 Radeberg, Germany; [email protected] 4 Center for Translational Neuromedicine, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen N, Denmark; [email protected] 5 School of Pharmacy, University of Oslo, Norwegian Medical Cyclotron Centre, N-0372 Oslo, Norway and Norwegian Medical Cyclotron Centre Ltd., Sognsvannsveien 20, N-0372 Oslo, Norway; [email protected] * Correspondence: [email protected] (P.C.); [email protected] (A.R.); Tel.: +41-31-664-04-98 (P.C.); +41-31-632-26-10 (A.R.) Academic Editor: Peter Brust Received: 21 October 2019; Accepted: 13 November 2019; Published: 19 November 2019 Abstract: The discovery of endogenous peptide ligands for morphine binding sites occurred in parallel with the identification of three subclasses of opioid receptor (OR), traditionally designated as µ, δ, and κ, along with the more recently defined opioid-receptor-like (ORL1) receptor. Early efforts in opioid receptor radiochemistry focused on the structure of the prototype agonist ligand, morphine, although N-[methyl-11C]morphine, -codeine and -heroin did not show significant binding in vivo. [11C]Diprenorphine ([11C]DPN), an orvinol type, non-selective OR antagonist ligand, was among the first successful PET tracers for molecular brain imaging, but has been largely supplanted in research studies by the µ-preferring agonist [11C]carfentanil ([11C]Caf). These two tracers have the property of being displaceable by endogenous opioid peptides in living brain, thus potentially serving in a competition-binding model. Indeed, many clinical PET studies with [11C]DPN or [11C]Caf affirm the release of endogenous opioids in response to painful stimuli. Numerous other PET studies implicate µ-OR signaling in aspects of human personality and vulnerability to drug dependence, but there have been very few clinical PET studies of µORs in neurological disorders. Tracers based on naltrindole, a | downloaded: 5.10.2021 non-peptide antagonist of the δ-preferring endogenous opioid enkephalin, have been used in PET studies of δORs, and [11C]GR103545 is validated for studies of κORs. Structures such as [11C]NOP-1A show selective binding at ORL-1 receptors in living brain. However, there is scant documentation of δ-, κ-, or ORL1 receptors in healthy human brain or in neurological and psychiatric disorders; here, clinical PET research must catch up with recent progress in radiopharmaceutical chemistry. Keywords: opioid receptors; positron emission tomography; radiotracers; µOR-, δOR-, κOR- and ORL1-ligands; epilepsy; movement disorders; pain; drug dependence 1. Introduction The analgesic and soporific properties of opium have been known since antiquity, perhaps first attested in the detached reveries of Homer’s Lotophagi. The sinister side of opium dreams is depicted https://doi.org/10.7892/boris.137421 in Tennyson’s version of that story, and more distinctly in the memoires of Thomas de Quincy, who may have had the distinction of establishing a genre of literature, the addiction diary. A key active constituent of the sap of Papaver somniferum was first isolated in 1804 by the apothecary Friedrich source: Molecules 2019, 24, 4190; doi:10.3390/molecules24224190 www.mdpi.com/journal/molecules MoleculesMolecules2019 2019, 24,, 24 4190, x 2 of2 36 of 35 Quincy, who may have had the distinction of establishing a genre of literature, the addiction diary. WilhelmA key active Sertürner, constituent who named of the sap it morphium, of Papaver somniferum later morphine was first (1). isolated Chemists in 1804 identified by the apothecary its elemental th compositionFriedrich Wilhelm in the 19 Sertürner,century, who and named efforts it to morphium, determine later its structure morphine were (1). Chemists rewarded identified in 1925, whenits Gullandelemental and composition Robinson [1 in] recommended the 19th century, a structureand efforts consistent to determine with its the structure characteristics were rewarded of morphine in and1925, codeine when and Gulland their and degradation Robinson [1] products. recommended Subsequent a structure investigations consistent with confirmed the characteristics the correctness of of themorphine analytically and codeine deduced and structure their degradation of morphine, products. culminating Subsequent in its totalinvestigations synthesis, confirmed achieved the in the 1950scorrectness by Gates of and the Tschudi analytically [2,3]. deduced The absolute structure stereochemistry of morphine, of culminating morphine’s in five its chiral total carbonssynthesis, (5, 6, 9, 13achieved and 14) in wasthe 1950s reported by Gates by Bentley and Tschudi and Cardwell [2,3]. The [ 4absolute] in 1955, stereochemistry and the first practicallyof morphine’s realizable five morphinechiral carbons total synthesis (5, 6, 9, with13 and reasonable 14) was reported yields was by reportedBentley and by RiceCardwell in 1980 [4] [ 5in]. To1955, this and day, the it isfirst more economicalpractically to realizable allow the morphine poppy plant total to synthesis do the main with work reasonable of morphine yields (was1) synthesis, reported althoughby Rice in chemists 1980 have[5]. since To this produced day, it is so more many economical structural to variants allow the that poppy one mightplant to consider do the main opioid work pharmacology of morphine to (1 be) a disciplinesynthesis, in itsalthough own right. chemists There have have since been produced several reviewsso many of structural opioid receptor variants imaging that one in might the past consider opioid pharmacology to be a discipline in its own right. There have been several reviews of decade [6–8], but we now present a comprehensive update on the the main classes of opioid receptor opioid receptor imaging in the past decade [6–8], but we now present a comprehensive update on (OR) ligands used for positron emission tomography (PET), and review clinical findings with this the the main classes of opioid receptor (OR) ligands used for positron emission tomography (PET), technology. Relevant chemical structures of endogenous opioid peptides and representative small and review clinical findings with this technology. Relevant chemical structures of endogenous moleculeopioid peptides opioid receptor and representative ligands are small depicted molecule in Figure opioid1. receptor ligands are depicted in Figure 1. 2 3 HO 1 A 4 11 O O O 10 H H O O O 12 15 B H H O E 16 N N N N 13 D N N OH 17 H H N N OH 5 14 9 NCH3 NH O O H H C H HO 2 NH2 O O 8 HO HO 6 7 S 1 2 3 Morphine Met5-enkephalin Leu5-enkephalin 5R, 6S, 9R, 13S, 14R O HO OH HO H CO O O 3 O O NCH3 N N N N HO OH OH OCH3 OH O O O N N 45 6 7 Oxycodone Naltrexone Cyprodime Naloxonazine FigureFigure 1. 1.Chemical Chemical structures structures of of endogenousendogenous opioid peptides peptides and and selected selected opioid opioid receptor receptor ligands. ligands. TheThe modern modern era era ofof opioidopioid pharmacology pharmacology began began with with the theidentification identification of an ofopioid an opioid binding binding site sitein in brain brain tissue tissue in studies in studies with withtritiated tritiated naloxone naloxone [9]. Soon [9 ].thereafter, Soon thereafter, opioid peptides opioid were peptides isolated were isolatedfrom frompig brain pig brain [10], [which10], which famously famously involved involved whisky whisky as an as emolument an emolument for forthe theslaughterhouse slaughterhouse 5 5 workers.workers. The The pentapeptides pentapeptides Met Met5-enkephalin-enkephalin ( (22)) and and Leu Leu5-enkephalin-enkephalin (3 () 3both) both had had morphine-like morphine-like effectseffects in inhibitingin inhibiting the electricallythe electrically stimulated stimulated contraction contraction of the ofvas the deferens vas deferens, with the, with latter the compound latter compound being somewhat less potent. The enkephalins were most abundant in striatum and being somewhat less potent. The enkephalins were most abundant in striatum and hypothalamus hypothalamus of rat, guinea pig and calf, and Met5-enkephalin (2) was generally 3–6 times more of rat, guinea pig and calf, and Met5-enkephalin (2) was generally 3–6 times more abundant than abundant than Leu5-enkephalin (3) [11,12]. An additional higher molecular weight opioid Leu5-enkephalin (3)[11,12]. An additional higher molecular weight opioid (β-endorphin) isolated and (β-endorphin) isolated and sequenced from camel pituitary extracts proved to be a 31 amino acid sequencedpolypeptide from possessing camel pituitary homology extracts with proved Met5-enkephalin to be a 31 amino (2) [13]. acid A polypeptidetrypsin-sensitive possessing opioid activity homology 5 with(dynorphin-A) Met -enkephalin isolated (2)[ 13from]. A trypsin-sensitivepituitary is a 17 opioid amino activity acid polypeptide (dynorphin-A) possessing isolated fromN-terminal pituitary 5 is ahomology 17 amino with acid polypeptideLeu5-enkephalin possessing (3), withN the-terminal shorter homology peptide dynorphin-B with Leu -enkephalin [1-13]

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