Imaging Synaptic Neurotransmission within VivoBinding Competition Techniques: A Critical Review

Abstract

Summary: Several groups have provided evidence that posi tron emission tomography (PET) and single-photon emission computed tomography (SPECT) neuroreceptor imaging tech niques might be applied to measure acute t1uctuations in do pamine (OA) synaptic concentration in the living human brain. Competition between OA and radioligands for binding to O2 receptor is the principle underlying this approach. This new application of neuroreceptor imaging provides a dynamic mea surement of neurotransmission that is likely to be informative to our understanding of neuropsychiatric conditions. This ar ticle reviews and discusses the body of data supporting the feasibility and potential of this imaging paradigm. Endogenous competition studies performed in rodents, nonhuman primates, and humans are first summarized. After this overview, the va lidity of the model underlying the interpretation of these im aging data is critically assessed. The current reference model is defined as the occupancy model, since changes in radiotracer binding potential (BP) are assumed to be directly caused by changes in occupancy of O2 receptors by OA. Experimental data supporting this model are presented. The evidence that manipulation of OA synaptic levels induces change in the BP of several O2 radiotracers (catecholamines and benzamides) is unequivocal. The fact that these changes in BP are mediated by changes in OA synaptic concentration is well documented. The relationship between the magnitude of BP changes measured with PET or SPECT and the magnitude of changes in OA concentration measured by microdialysis supports the use of these noninvasive techniques to measure changes in neuro transmission. On the other hand, several observations remain unexplained. First, the amphetamine-induced changes in the BP of O2 receptor antagonists [1 2 3IJIBZM and [I I Clraclopride last longer than amphetamine-induced changes in OA extracellular concentration. Second, nonbenzamide O2 receptor antagonists, such as spiperone and pimozide, are not affected by changes in OA release, or are affected in a direction opposite to that pre dicted by the occupancy model. Similar observations are re ported with 0 I radiotracers. These results suggest that the changes in BP following changes in OA concentration might not be fully accounted by a simple occupancy model. Specifi cally, the data are reviewed supporting that agonist-mediated receptor internalization might play an important role in char acterizing receptor-ligand interactions. Finally, it is proposed that a better understanding of the mechanism underlying the effects observed with benzamides is essential to develop this imaging technique to other receptor systems. Key Words: Pos itron emission tomography-Single-photon emission computed tomography-Oopamine-Raclopride-IBZM-Spiperone Internalization.Received August 2S, 1999; final revision received December 3, 1999; accepted December 3, 1999. Supported by the National Institute of Mental Health (K02 MHO I 603-0 1). Address correspondence and reprint requests to Ma...

Modulation of Amphetamine-Induced Dopamine Release by Group II Metabotropic Glutamate Receptor Agonist LY354740 in Non-Human Primates Studied with Positron Emission Tomography

“…The reason for this apparent discrepancy is that the DAT are effective at preventing the diffusion of synaptic DA to the extracellular space (Tsukada et al, 2000). Thus, [ 11 C]raclopride imaging provides a more direct measure of D 2 receptor stimulation by DA than microdialysis (see, for further discussion, Laruelle, 2000). In addition, this method is noninvasive, and similar experiments can be conducted in animals and humans.…”

“…It should however be pointed out that the duration of the effect of amphetamine on [ 11 C]raclopride or [ 123 I]IBZM V 3 00 exceeds the duration of the increase in extracellular DA (Laruelle et al, 1997). This observation suggests that mechanisms other than simple binding competition, such as DA-induced receptor internalization, are involved in this response (see, for further discussion, Laruelle, 2000).…”

Evaluation of Dopamine D-2 Receptor Occupancy by Clozapine, Risperidone, and Haloperidol In Vivo in the Rodent and Nonhuman Primate Brain Using 18F-Fallypride

“…Thus, competition of the various drugs with dopamine for the high-affinity state can be a significant issue. It has been suggested that 20% of the D-2 receptors are occupied by dopamine and 30% of the receptor sites are vulnerable to increases in dopamine (Laruelle 2000).…”

News and views on in-vivo imaging of neurotransmission using PET and MRI

“…Several radiotracers for both the excitatory D1-like receptors (D1/D5) and the inhibitory D2-like receptors (D2/D3/D4) have been tested for sensitivity to endogenous dopamine in animals or humans using 11 C or 18 F-labeled compounds. The substituted benzamide derivative [ 11 C]raclopride has consistently been shown to display changes in binding which are consistent with dopamine competition 3 . More recently, antagonist radiotracers with higher D2 receptor affinity compared to raclopride, such as [ 11 C]FLB457 and [ 18 F]fallypride, have been used to investigate extrastriatal brain regions, where the density of D2 receptor is much lower than in the striatum.…”