Circulation, Vol 82, 1494-1504, Copyright © 1990 by American Heart Association
J Delforge, M Janier, A Syrota, C Crouzel, JM Vallois, J Cayla, JP Lancon and BM Mazoyer
The in vivo quantification of myocardial muscarinic receptors has been
obtained in six closed-chest dogs by using positron emission tomography.
The dogs were injected with a trace amount of 11C-labeled
methylquinuclidinyl benzilate (MQNB), a nonmetabolized antagonist of the
muscarinic receptor. This was followed 30 minutes later by an injection of
an excess of unlabeled MQNB (displacement experiment). Two additional
injections of unlabeled MQNB with [11C]MQNB (coinjection experiment) and
without [11C]MQNB (second displacement experiment) were administered after
70 and 120 minutes, respectively. This protocol allowed a separate
evaluation of the quantity of available receptors (B'max) as well as the
association and dissociation rate constants (k+1 and k-1) in each dog. The
parameters were calculated by using a nonlinear mathematical model in
regions of interest over the left ventricle and the interventricular
septum. The average value of B'max was 42 +/- 11 pmol/ml tissue, the rate
constants k+1, k-1, and Kd were 0.6 +/- 0.1 ml.pmol-1.min-1, 0.27 +/- 0.03
ml.pmol-1.min-1, and 0.49 +/- 0.14 pmol.ml-1, respectively, taking into
account the MQNB reaction volume estimated to 0.15 ml/ml tissue. Although
[11C]MQNB binding would appear irreversible, our findings indicate that the
association of the antagonist is very rapid and that the dissociation is
far from negligible. The dissociated ligand, however, has a high
probability of rebinding to a free receptor site instead of escaping into
the microcirculation. We deduce that the positron emission tomographic
images obtained after injecting a trace amount of [11C]MQNB are more
representative of blood flow than of receptor density or affinity. We also
suggest a simplified protocol consisting of a tracer injection of [11C]MQNB
and a second injection of an excess of cold MQNB, which is sufficient to
measure B'max and Kd in humans.
ARTICLES
Noninvasive quantification of muscarinic receptors in vivo with positron emission tomography in the dog heart
Service Hospitalier Frederic Joliot, Commissariat a l'Energie Atomique, Orsay, France.
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