title: Absolute quantification by positron emission tomography of the endogenous ligand.
abstract: The results of several recent papers have shown a significant influence of the endogenous neurotransmitters on the exogenous ligand kinetics measured by positron emission tomography. For example, several groups found that the percentage of D2 receptor sites occupied by the endogenous dopamine ranged from 25% to 40% at basal level. An obvious consequence of this significant occupancy is that the ligand-receptor model parameters, usually estimated by a model that does not take into account the endogenous ligand (EL) kinetics, can be significantly biased. In the current work, the authors studied the biases obtained by using the multiinjection approach. The results showed that in the classical ligand-receptor model, the receptor concentration is correctly estimated and that only the apparent affinity is biased by not taking the EL into account. At present, all absolute quantifications of the EL have been obtained through pharmacologic manipulation of the endogenous transmitter concentration, which is often too invasive a method to be used in patients. A theoretical reasoning showed that a noninvasive approach is necessarily based on both the apparent affinity measurement and on a multiregion approach. The correlation between the receptor concentration and the apparent affinity, previously observed with some ligands, verifies these two conditions; thus, the authors suggest that this correlation could be the result of the EL effect. To test this assumption experimentally, the effect of reserpine-induced dopamine depletion on the interactions between the D2 receptor sites and the FLB 457 is studied. With untreated baboons, the apparent FLB 457 affinity was smaller in the receptor-rich regions (striatum) than in the receptor-poor regions. This discrepancy disappeared after dopamine depletion, strongly suggesting that this affinity difference was related to the EL effect. Therefore, the purpose of the current study was to test the ability to quantify the EL based on the observed correlation between the receptor concentration and the apparent affinity. This approach offers a method for estimating the percentage of receptor sites occupied by the EL and, if its affinity is known, the free EL concentration. From the data obtained using FLB 457 with baboons, the authors found that approximately 53% of the D2 receptor sites are occupied by dopamine in the striatum and that the free dopamine concentration is approximately 120 nmol/L at basal level. This approach is transferable to patients, because the experimental data are obtained without pharmacologically induced modification of the EL.
authors.affiliation: Service Hospitalier Frédéric Joliot, Commissariat à l'Energie Atomique, Orsay, France.
authors.forename: J
authors.initials: J
authors.lastname: Delforge
authors.forename: M
authors.initials: M
authors.lastname: Bottlaender
authors.forename: S
authors.initials: S
authors.lastname: Pappata
authors.forename: C
authors.initials: C
authors.lastname: Loc'h
authors.forename: A
authors.initials: A
authors.lastname: Syrota
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism; D018492:Dopamine Antagonists / Q000378:metabolism; D005442:Flumazenil / Q000008:administration & dosage / Q000378:metabolism; D018757:GABA Modulators / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008024:Ligands; D008433:Mathematics; D008954:Models, Biological; D018377:Neurotransmitter Agents / Q000378:metabolism*; D010215:Papio; D011759:Pyrrolidines / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D017981:Receptors, Neurotransmitter / Q000378:metabolism*; D012110:Reserpine / Q000494:pharmacology; D012457:Salicylamides / Q000378:metabolism; D014055:Tomography, Emission-Computed
chemical_list: D018759:Adrenergic Uptake Inhibitors; D018492:Dopamine Antagonists; D018757:GABA Modulators; D008024:Ligands; D018377:Neurotransmitter Agents; D011759:Pyrrolidines; D017448:Receptors, Dopamine D2; D017981:Receptors, Neurotransmitter; D012457:Salicylamides; C065065:FLB 457; D005442:Flumazenil; D012110:Reserpine; D004298:Dopamine