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PET quantification of muscarinic cholinergic receptors with [N‐ 11 C‐methyl]‐benztropine and application to studies of propofol‐induced unconsciousness in healthy human volunteers
Author(s) -
Xie Guoming,
Gunn Roger N.,
Dagher Alain,
Daloze Thierry,
Plourde Gilles,
Backman Steven B.,
Diksic Mirko,
Fiset Pierre
Publication year - 2004
Publication title -
synapse
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.809
H-Index - 106
eISSN - 1098-2396
pISSN - 0887-4476
DOI - 10.1002/syn.10292
Subject(s) - muscarinic acetylcholine receptor , chemistry , benztropine , unconsciousness , muscarinic acetylcholine receptor m2 , muscarinic acetylcholine receptor m4 , receptor , endocrinology , anesthesia , biochemistry , medicine , dopamine
This work evaluated kinetic analysis methods for estimation of the receptor availability of the muscarinic receptor using dynamic positron emission tomography (PET) studies with [N‐ 11 C‐methyl]‐benztropine. The study also investigated the effect of propofol on central muscarinic receptor availability during general anesthesia. Six volunteers were scanned three times, once for baseline while awake, once during unconsciousness, and once after recovery to conscious level. An irreversible two‐tissue compartment model was used to estimate the [N‐ 11 C‐methyl]‐benztropine specific binding rate constant k 3 , a measure of muscarinic receptor availability. Two different estimation methods were used: 1) optimization with positivity constraints on all the parameters; 2) optimization with additional constraints determined from a one‐tissue compartment fit to the cerebellum. In regions with low to middle muscarinic receptor density, the k 3 values from method (2) had lower standard errors than that for method (1) and gave a higher correlation with the density of muscarinic receptors measured in human tissue by in vitro studies ( r 2 of 0.98 for Method 2 and r 2 of 0.72 for Method 1). But the k 3 values determined by Method 2 had higher errors for regions with high muscarinic receptor density compared to Method 1. For both methods the mean k 3 values during unconsciousness were generally lower than those during awake for most regions evaluated. Therefore, the method with additional constraints derived from the cerebellum (Method 2) was deemed superior for regions with low to middle muscarinic receptor density, while the method with positivity constraint is the better choice in the regions with high muscarinic receptor density. Our results also suggest the existence of propofol‐related reductions in muscarinic receptor availability. Synapse 51:91–101, 2004. © 2003 Wiley‐Liss, Inc.