Brain Incorporation of [11C]Arachidonic Acid in Young Healthy Humans Measured With Positron Emission Tomography

Abstract

Arachidonic acid (AA) is an important second messenger involved in signal transduction mediated by phospholipase A2. The goal of this study was to establish an in vivo quantitative method to examine the role of AA in this signaling process in the human brain. A simple irreversible uptake model was derived from rat studies and modified for positron emission tomography (PET) to quantify the incorporation rate K* of [11C]AA into brain. Dynamic 60-minute three-dimensional scans and arterial input functions were acquired in 8 young healthy adults studied at rest. Brain radioactivity was corrected for uptake of the metabolite [11C]CO2. K* and cerebral blood volume (Vb) were estimated pixel-by-pixel and were calculated in regions of interest. K* equaled 5.6+/-1.2 and 2.6+/-0.5 microL x min(-1) x mL(-1) in gray and white matter, respectively. K* and Vb values were found to be unchanged with data analysis periods from 20 to 60 minutes. Thus, PET can be used to obtain quantitative images of the incorporation rate K* of [11C]AA in the human brain. As brain incorporation of labeled AA has been shown in awake rats to be increased by pharmacological activation associated with phospholipase A2-signaling, PET and [11C]AA may be useful to measure signal transduction in the human brain.

[P3–317]: DHA BRAIN UPTAKE AND APOE4 STATUS: A PET STUDY WITH [1‐11C]‐DHA

“…The lower value of k* in the medial temporal cortex is consistent with previous reports for [1-11 C]-arachidonic acid and with values for rCBF [29,30]. The data likely reflect the unique architecture of this region, although there is some effect of the PVE correction [24].…”

D-Amphetamine Stimulates D2Dopamine Receptor-Mediated Brain Signaling Involving Arachidonic Acid in Unanesthetized Rats

“…It now is possible to measure k* for AA in the human brain with positron emission tomography (PET) following the intravenous injection of [1-11 C]AA (Esposito et al, 2003;Giovacchini et al, 2002Giovacchini et al, , 2004Rapoport et al, 2005). Thus, one might image D 2 -like receptor-mediated activation of AA metabolism in human brain diseases thought to have disturbed DA neurotransmission, such as Parkinson disease (Chalon et al, 1999;Hayakawa et al, 1998Hayakawa et al, , 2001Ross et al, 2001), cocaine abuse (Ross et al, 1996), attention deficit hyperactivity disorder and schizophrenia (Matochik et al, 1993;Wolkin et al, 1994).…”

Mode of action of mood stabilizers: is the arachidonic acid cascade a common target?

“…71 Quantitative autoradiography also allows one to determine incorporation coefficients for unesterified fatty acids from plasma into brain phospholipids within specific brain regions. With the synthesis of positron emitting 11 C fatty acids, similar to quantitative autoradiography, it is possible to measure the net uptake of unesterified fatty acids from plasma into brain regions in non-human primates 72 and in humans, 73,74 using positron emission tomography (PET). For the nutritionally essential polyunsaturated fatty acids AA and DHA, this net uptake from the plasma unesterified pool approximates the rate of metabolic breakdown (loss) from the brain.…”

“…As noted by the authors, the functional implications of such changes as well as knowledge of the patient's mood state at time of death will be important for future studies. To date, no 11 C AA PET studies, which are feasible, [72][73][74] have been completed in patients with bipolar disorder or subjects chronically administered mood stabilizers. Because of the limitations in using peripheral markers to proxy brain AA kinetics, the completion of these studies will be important in connecting some of the preclinical observations (Table 2) to patients with bipolar disorder.…”

“…166,167 After testing candidate drugs at the preclinical level, PET with 11 C-labeled AA and DHA could be used to study the metabolism of these polyunsaturated fatty acids in bipolar disorder patients and to proxy the effectiveness of candidate drugs in healthy humans. [72][73][74] Furthermore, drugs or conditions known to induce mania in susceptible individuals 171 could be studied using 11 C-labeled AA and PET. Because antidepressants can induce switching to mania when given to a depressed bipolar disorder patient, 146,[172][173][174] we examined the selective serotonin reuptake inhibitor fluoxetine in our models.…”