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Title: Imaging cholinergic function in vivo in the brain with radioiodinated stereoisomers of quinuclidinyl benzilate
Author: Paterson, David S.
ISNI:       0000 0001 3476 7144
Awarding Body: University of Glasgow
Current Institution: University of Glasgow
Date of Award: 1998
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This thesis evaluates the ability of (R,S)- and (R,R)-[125I]-QNB, two radioiodinated diastereoisomers of the high affinity muscarinic antagonist quinuclidinyl benzilate (QNB), to image dynamic changes in cholinergic function in the central nervous system using in vivo autoradiography. The regional uptake and retention of (R,S)-[125I]-QNB in the rat brain between 2 and 24 hours after intravenous administration was investigated to assess the utility of this technique to image muscarinic receptors in the central nervous system. Similarly, the uptake and retention of (R,R)-[125I]-QNB was investigated between 30 mins and 6 hours after administration using in vivo autoradiography and was compared to that of (R,S)-[125I]-QNB. Secondly, the sensitivity of (R,S)- and (R,R)-[125I]-QNB to dynamic changes in cholinergic neurotransmission in vivo, was assessed in conscious rats. The uptake and retention of (R,S)- and (R,R)-[125I]-QNB following a cholinergic challenge produced by administration of the long lasting AChE inhibitor heptylphysostigmine, was investigated. Regional brain levels of (R,S)- and (R,R)-[125I]-QNB in heptylphysostigmine treated animals were compared to levels in saline treated animals by in vivo autoradiography. The ability of ACh to displace (R,S)- and (R,R)-[125I]-QNB binding from rat brain sections in vitro in the presence of heptylphysostigmine was also investigated. Finally, the effects of heptylphysostigmine administration on regional cerebral blood flow were investigated using [14C]-IAP autoradiography in conscious rats. Three hypotheses were considered to account for the lack of radioligand displacement observed following heptylphysostigmine administration: 1) Heptylphysostigmine was ineffective in inhibiting AChE and raising synaptic ACh levels at the dosage used in this thesis. 2) A small amount of displacement occurred but was masked by the effects of increased cerebral blood flow. 3) (R,S)- and (R,R)-[125I]-QNB are of too high affinity for mAChRs to be displaced by endogenous neurotransmitter. The third hypothesis is viewed as the most plausible. In conclusion, (R,S)- and (R,R)-[125I]-QNB are unsuitable ligands for the detection of cholinergic function in vivo.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry