Noninvasive quantification of muscarinic receptors in vivo with positron emission tomography in the dog heart

J Delforge, M Janier, A Syrota, C Crouzel, J M Vallois, J Cayla, J P Lançon, B M Mazoyer
1990 Circulation  
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'C-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 ['1C]MQNB (coinjection experiment) and without
more » ... I1C]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'nax) as well as the association and dissociation rate constants (k+l and kL1) 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'iax was 42+11 pmol/ml tissue, the rate constants k+l, kl"and Kd were 0.6±0.1 ml pmol-' min', 0.27±0.03 ml * pmol' ' min', and 0.49+0.14 pmol* ml-', respectively, taking into account the MQNB reaction volume estimated to 0.15 ml/ml tissue. Although ['C]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 ['C]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 ["C'MQNB and a second injection of an excess of cold MQNB, which is sufficient to measure B'ax and Kd in humans. (Circulation 1990;82:1494-1504 M auscarinic cholinergic receptors play a key role in the regulation of the rate and force of contraction of the heart, and various changes in receptor number and affinity occur in various physiological, pharmacological, and clinical conditions in animals and humans.1-8 The development and use of radioligands with high affinity and specificity to the muscarinic receptor has greatly contributed to our knowledge of the receptor biochemistry.9 Various tritium-labeled antagonists such as quinuclidinyl benzilate (QNB), atropine, dexetimide, N-methylscopolamine (NMS), or N-From the Service
doi:10.1161/01.cir.82.4.1494 pmid:2401078 fatcat:c3l3yhstbbdcnbfx6dcec7rlcq