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  • 1
    ISSN: 1432-2072
    Keywords: SPECT ; Dopamine receptors ; NCQ 298 ; Iodinated radioligand ; Salicylamide
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract NCQ 298 ((S)-3-iodo-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5,6-dimethoxysalicylamide) has an iodine substituent. We have labelled NCQ 298 with123I and125I, and used the radioligands as tracers in receptor studies in vitro, in vivo in autoradiography and in SPECT studies on Cynomolgus monkeys. [125I]NCQ 298 bound in vitro to a single binding site with a KD=19 pM. NCQ 298 has thus a 10-fold higher affinity for the dopamine D2 receptors than the corresponding des-5-methoxy compound FLA 961 (IBZM), previously used in SPECT studies. The binding of [125I]NCQ 298 was entirely reversible (T1/2=17.5 min at 37° C). Autoradiographical studies in vitro on rat and monkey brain tissue sections showed a distinct binding in caudate-putamen, nucleus accumbens, substantia nigra, and in layer 5 of the cerebral cortex. In vivo binding studies in mice showed a ratio of 10 between [125I]NCQ 298 binding in striatum and cerebellum. Binding was displaced by the selective dopamine D2 receptor antagonist raclopride. In SPECT studies with [123I]NCQ 298 in two Cynomolgus monkeys, radioactivity accumulated in the basal ganglia. The measured striatum to cerebellum ratio was about 15 after 3 h. A monkey brain phantom was constructed for the determination of conversion factors from pixel events to actual radioactivity. The resulting, corrected striatum to cerebellum ratio obtained was 30. After administration of 12 mg raclopride to one of the monkeys there was a substantial decrease in striatal radioactivity. [125I]NCQ 298 is a suitable ligand for the labelling of dopamine D2 receptors in vitro and in vivo. The specific properties of [123I]NCQ 298 suggest that this compound is a useful ligand for quantitative SPECT studies of dopamine D2 receptors in man.
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  • 2
    ISSN: 1432-2072
    Keywords: Key words Z-IQNP ; SPECT ; Autoradiography ; Alzheimer’s disease ; Muscarinic acetylcholine receptor
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: The density of the M2 subtype of muscarinic acetylcholine receptors (mAChR) has been shown to be reduced in the brain of patients with Alzheimer’s disease (AD). It is therefore of interest to develop a brain imaging method for diagnostic purposes. Z-(R,R)-1-azabicyclo[2.2.2]oct-3-yl α-hydroxy-α-(1-iodo-1-propen-3-yl)-α-phenylacetate (Z-IQNP) is a muscarinic antagonist with high affinity for the M2 subtype. Objective: The pharmacological characteristics and topographic distribution of radiolabelled Z-IQNP as a radioligand for the M2 mAChR subtype were examined in vitro and in vivo. Methods: Z-IQNP was labelled with 125I and 123I. Autoradiography was performed on whole-hemisphere cryosections from human post mortem brains. SPECT was performed in a cynomolgus monkey. Results: Autoradiography showed binding of [125I]Z-IQNP in all brain regions, which was inhibited by the non-selective muscarinic antagonist scopolamine. The addition of BIBN 99, a compound with high affinity for the M2 subtype, inhibited [125I]Z-IQNP binding particularly in the cerebellum, which has a high density of the M2 subtype. SPECT demonstrated high uptake of [123I]Z-IQNP in all brain regions. The binding was markedly reduced in all brain regions after pretreatment with the non-selective muscarinic antagonist dexetimide and also the M1 antagonist biperiden. Dexetimide markedly inhibited [123I]Z-IQNP binding in the cerebellum, which is consistent with a high density of M2-receptors in this region. The sigma receptor binding compound DuP 734 had no effect on Z-IQNP binding either in vitro or in vivo. Conclusions: This study indicates that radiolabelled Z-IQNP has high specificity for mAChR with higher affinity for the M2 than the M1 subtype and negligible affinity for sigma recognition sites both in vitro and in vivo. [123I]Z-IQNP should be useful for future SPECT studies in AD for examination of the density of M2 receptors particularly in the cerebellum.
    Type of Medium: Electronic Resource
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