Dopamine D(2) receptors, similar to other G-protein-coupled receptors, exist in a high- and low-affinity state for agonists. Based upon a review of the methods for detecting D(2) receptor agonist high-affinity states, we discuss alterations of such states in animal models of disease and the implications of such alterations for their labelling with positron emission tomography (PET) and single-photon emission computed tomography (SPECT) tracers. The classic approach of detecting agonist high-affinity states compares agonist competition for antagonist radioligands, in most cases using [(3)H]-spiperone as the radioligand; alternative approaches and radioligands have been proposed, but their claimed advantages have not been substantiated by other investigators. In view of the advantages and disadvantages of various techniques, we critically have reviewed reported findings on the detection of D(2) receptor agonist high-affinity states in a variety of animal models. These data are compared to the less numerous findings from human in vivo studies based on PET and SPECT tracers; they are interpreted in light of the finding that D(2) receptor agonist high-affinity states under control conditions may differ between rodent and human brain. The potential advantages of agonist ligands in studies of pathophysiology and as diagnostics are being discussed.

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The muscarinic M 1 receptor (M 1 R) is highly involved in cognition, and selective M 1 agonists have procognitive properties. Loss of M 1 R has been found in postmortem brain tissue for several neuropsychiatric disorders and may be related to symptoms of cognitive dysfunction. 123 I-iododexetimide is used for imaging muscarinic acetylcholine receptors (mAchRs). Considering its high brain uptake and intense binding in M 1 R-rich brain areas, 123 I-iododexetimide may be an attractive radiopharmaceutical to image M 1 R. To date, the binding affinity and selectivity of 123 I-iododexetimide for the mAchR subtypes has not been characterized, nor has its brain distribution been studied intensively. Therefore, this study aimed to address these topics. Methods: The in vitro affinity and selectivity of 127 I-iododexetimide (cold-labeled iododexetimide), as well as its functional antagonist properties (guanosine 5′-[γ-35 S-thio]triphosphate [GTPγ 35 S] assay), were assessed on recombinant human M 1 R-M 5 R. Distributions of 127 I-iododexetimide and 123 I-iododexetimide in the brain were evaluated using liquid chromatography-mass spectrometry and storage phosphor imaging, respectively, ex vivo in rats, wild-type mice, and M 1 -M 5 knock-out (KO) mice. Inhibition of 127 I-iododexetimide and 123 I-iododexetimide binding in M 1 R-rich brain areas by the M 1 R/ M 4 R agonist xanomeline, or the antipsychotics olanzapine (M 1 R antagonist) and haloperidol (low M 1 R affinity), was assessed in rats ex vivo. Results: In vitro, 127 I-iododexetimide displayed high affinity for M 1 R (pM range), with modest selectivity over other mAchRs. In biodistribution studies on rats, ex vivo 127 I-iododexetimide binding was much higher in M 1 R-rich brain areas, such as the cortex and striatum, than in cerebellum (devoid of M 1 Rs). In M 1 KO mice, but not M 2 -M 5 KO mice, 127 I-iododexetimide binding was strongly reduced in the frontal cortex compared with wild-type mice. Finally, acute administration of both an M 1 R/M 4 R agonist xanomeline and the M 1 R antagonist olanzapine was able to inhibit 123 I-iododexetimide ex vivo, and 123 I-iododexetimide binding in M 1 -rich brain areas in rats, whereas administration of haloperidol had no effect. Conclusion: The current results suggest that 123 I-iododexetimide preferentially binds to M 1 R in vivo and can be displaced by M 1 R ligands. 123 I-iododexetimide may therefore be a useful imaging tool as a way to further evaluate M 1 R changes in neuropsychiatric disorders, as a potential stratifying biomarker, or as a clinical target engagement biomarker to assess M 1 R.