Positron emission tomography imaging of amphetamine‐induced dopamine release in the human cortex: A comparative evaluation of the high affinity dopamine D_2/3 radiotracers [¹¹C]FLB 457 and [¹¹C]fallypride

Abstract

The use of PET and SPECT endogenous competition binding techniques has contributed to the understanding of the role of dopamine in several neuropsychiatric disorders. An important limitation of these imaging studies is the fact that measurements of acute changes in synaptic dopamine have been restricted to the striatum. The ligands previously used, such as [(11)C]raclopride and [(123)I]IBZM, do not provide sufficient signal to noise ratio to quantify D(2) receptors in extrastriatal areas, such as cortex, where the concentration of D(2) receptors is much lower than in the striatum. Given the importance of cortical DA function in cognition, a method to measure cortical dopamine function in humans would be highly desirable. The goal of this study was to compare the ability of two high affinity DA D(2) radioligands [(11)C]FLB 457 and [(11)C]fallypride to measure amphetamine-induced changes in DA transmission in the human cortex. D(2) receptor availability was measured in the cortical regions of interest with PET in 12 healthy volunteers under control and postamphetamine conditions (0.5 mg kg(-1), oral), using both [(11)C]FLB 457 and [(11)C]fallypride (four scans per subjects). Kinetic modeling with an arterial input function was used to derive the binding potential (BP(ND)) in eight cortical regions. Under controlled conditions, [(11)C]FLB 457 BP(ND) was 30-70% higher compared with [(11)C]fallypride BP(ND) in cortical regions. Amphetamine induced DA release led to a significant decrease in [(11)C]FLB 457 BP(ND) in five out the eight cortical regions evaluated. In contrast, no significant decrease in [(11)C]fallypride BP(ND) was detected in cortex following amphetamine. The difference between [(11)C]FLB 457 and [(11)C]fallypride ability to detect changes in the cortical D(2) receptor availability following amphetamine is related to the higher signal to noise ratio provided by [(11)C]FLB 457. These findings suggest that [(11)C]FLB 457 is superior to [(11)C]fallypride for measurement of changes in cortical synaptic dopamine.

It still hurts: altered endogenous opioid activity in the brain during social rejection and acceptance in major depressive disorder

“…“MOR activation” was defined as the reduction in MOR binding potential from baseline to rejection or acceptance block (i.e., baseline-rejection, baseline-acceptance). This metric represents competition between radiotracer and endogenous opioids, changes in the conformational state of the receptor after activation, and/or changes in receptor concentration (e.g., via internalization, trafficking), all of which are related to endogenous opioid neurotransmission 40,41 .…”

Serotonin and molecular neuroimaging in humans using PET

“…Measuring endogenous serotonin levels with PET is of high relevance, seeing the successful and informative implementation of such measurements in the dopaminergic system (e.g., Narendran et al 2009). It has proven difficult, though, to translate this success to the serotonergic system.…”

Extrastriatal dopaminergic abnormalities of DA homeostasis in Parkinson's patients with medication-induced pathological gambling: A [11C] FLB-457 and PET study

“…We reasoned that differences between patients with and without PG might be elevated when on pramipexole, since a single dose of 1 mg pramipexole has previously been shown to alter behaviour even in drug naïve individuals (Campbell-Meiklejohn et al, 2011). PET images were acquired using [11C] FLB-457, a high affinity marker used for assaying extrastriatal D2/D3 receptors (Farde et al, 1997), and which has been shown to be sensitive to endogenous DA levels in the PFC and midbrain (Montgomery et al, 2007;Narendran et al, 2009;Vandehey et al, 2010). PET scans were obtained with a high resolution PET CT, Siemens-Biograph HiRez XVI (Siemens Molecular Imaging, Knoxville, TN, U.S.A.) operating in 3D mode with an inplane resolution of approximately 4.6 mm full width at half-maximum.…”