Abstract
As a reported agonist,11C-CUMI-101 is believed to selectively bind the G-protein-coupled state of the serotonin-1A (5-HT1A) receptor, thereby providing a measure of the active subset of all 5-HT1A receptors in brain. Although 11C-CUMI-101 has been successfully used to quantify 5-HT1A receptors in human and monkey brain, its radiation exposure has not previously been reported. The purpose of this study was to calculate the radiation exposure to organs of the body based on serial whole-body imaging with positron emission tomography (PET) in human subjects.MethodsNine healthy volunteers were injected with 428±84 MBq (mean ± SD) 11C-CUMI-101 and then imaged with a PET-only device for two hours from head to mid-thigh. Eleven source organs (brain, heart, liver, pancreas, stomach, spleen, lungs, kidneys, lumbar spine L1-5, thyroid, and urinary bladder) were identified on whole body images and used to calculate radiation doses using the software program OLINDA/EXM 1.1. To confirm that we had correctly identified the pancreas, a tenth subject was imaged on a PET/CT device.ResultsBrain had high uptake (∼11% of injected activity (IA)) at 10 min. Although liver had the highest uptake (∼35% IA at 120 min), excretion of this activity was not visible in gall bladder or intestine during the scanning session. Organs which received the highest doses (microSv/MBq) were pancreas (32.0), liver (18.4), and spleen (14.5). The effective dose of 11C-CUMI-101 was 5.3±0.5 microSv/MBq.ConclusionThe peak brain uptake (∼11% IA) of 11C-CUMI-101 is the highest among more than twenty 11C-labeled ligands reported in the literature and provides good counting statistics from relatively low injected activities. Similar to that of other 11C-labeled ligands for brain imaging, the effective dose of 11C-CUMI-101 is 5.3±0.5 microSv/MBq, a value that can now be used to estimate the radiation risks in future research studies.
Highlights
For G-protein-coupled receptors, antagonists generally bind with equal affinity to the coupled and uncoupled states, but agonists bind preferentially to the coupled, or active, state of the receptor [1]
Agonist radioligands for the dopamine D2 receptor have been used to assess the effects of stimulant-induced dopamine release [3] and agonist-induced internalization of the receptor [4]
The first agonist radioligand introduced for studying a serotonin receptor in human brain with positron emission tomography (PET) was CUMI-101: [O-methyl-11C]2-(4-(4-(2-methoxyphenyl)piperazine-1-yl)butyl)-4-methyl-1,2,4-triazine-3,5(2H,4H)dione) [5]
Summary
For G-protein-coupled receptors, antagonists generally bind with equal affinity to the coupled and uncoupled states, but agonists bind preferentially to the coupled, or active, state of the receptor [1]. The first agonist radioligand introduced for studying a serotonin receptor in human brain with PET (positron emission tomography) was CUMI-101: [O-methyl-11C]2-(4-(4-(2-methoxyphenyl)piperazine-1-yl)butyl)-4-methyl-1,2,4-triazine-3,5(2H,4H)dione) [5]. CUMI-101 is a partial agonist at 5-HT1A receptors based on its actions on adenylate cyclase and its action on binding of [35S]GTPcS binding to cultured cells with the human receptor [5]. CUMI-101 is reported to be selective for 5-HT1A receptor with an inhibition constant (Ki) of 0.15 nM [5]. The uptake of 11C-CUMI-101 in monkey brain matches the distribution of 5-HT1A receptors and can be displaced by 5-HT1A receptor-specific ligands [5,6]. The uptake of 11C-CUMI-101 in human brain has recently been quantified relative to serial concentrations of the radioligand in arterial plasma using compartmental modeling [7,8]
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