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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 &#956;, &#948;, and &#954;, 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 <i>N</i>-[methyl-¹¹C]morphine, -codeine and -heroin did not show significant binding <i>in vivo</i>. [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 &#956;-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 &#956;-OR signaling in aspects of human personality and vulnerability to drug dependence, but there have been very few clinical PET studies of &#956;ORs in neurological disorders. Tracers based on naltrindole, a non-peptide antagonist of the &#948;-preferring endogenous opioid enkephalin, have been used in PET studies of &#948;ORs, and [¹¹C]GR103545 is validated for studies of &#954;ORs. Structures such as [¹¹C]NOP-1A show selective binding at ORL-1 receptors in living brain. However, there is scant documentation of &#948;-, &#954;-, 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.