RT Journal Article
SR Electronic
T1 A novel PET radioligand, [11C]PS13, successfully images COX-1, a potential biomarker for neuroinflammation.
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP 115
OP 115
VO 57
IS supplement 2
A1 Stal Shrestha
A1 Prachi Singh
A1 Mark Eldridge
A1 Michelle Cortes
A1 Robert Gladding
A1 Cheryl Morse
A1 Sami Zoghbi
A1 Masahiro Fujita
A1 Jeih-San Liow
A1 Victor Pike
YR 2016
UL http://jnm.snmjournals.org/content/57/supplement_2/115.abstract
AB 115Objectives Cyclooxygenase-1 (COX-1) is mainly located in activated microglia, and is considered to be an important player in mediating brain inflammation in neuropsychiatric disorders. As such, COX-1 is a potential biomarker for neuroinflammation. An effective PET radioligand for measuring human brain COX­-1 density would be a potentially valuable tool for biomedical research. Here we report on the development of a promising PET radioligand for brain COX-1 in monkey.Methods We synthesized and screened 17 triazole derivatives for inhibitory potency at COX­-1 and COX­-2 using whole blood from monkey and human. The compound exhibiting most favorable COX-1 affinity, COX-1 selectivity, and lipophilicity, dubbed PS13 (1,5-bis(4-methoxyphenyl)-3-(2,2,2-trifluoroethoxy)-1H -1,2,4 trazole) was labeled with C-11 by treatment of its O-desmethyl precursor with no-carrier-added [C-11]iodomethane and then separated in > 99% radiochemical purity. [C-11]PS13 (~ 190 GBq/µmol) was intravenously injected into 8 male rhesus monkeys at baseline, and 3 h later at ~ 3 min after administration of a COX-1 blocking agent (either PS13 or ketoprofen as its methyl ester, KTPMe; each at three doses: 3, 0.3, and 0.03 mg/kg i.v.). Dynamic PET scans of brain were acquired on a Focus 220 scanner for 2 h, concurrent with frequent sampling of arterial blood to measure the concentration of unmetabolized radioligand. Brain volume of distribution (VT) was estimated by applying a two-tissue compartmental model to the PET and blood data. In other monkey experiments, an inflammogen (LPS) or an excitotoxin (ibotenic acid) was injected into one side of the basal ganglia to induce transient localized inflammation. We then performed PET scans with [C-11]PS13, [C-11]PBR28 (a TSPO radioligand), and [C-11]KTPMe (a prodrug type COX­-1 radioligand in current use) to determine the time-course of neuroinflammation.Results The in vitro assays demonstrate that PS13 has high affinity and high selectivity for both monkey and human COX­-1 (IC50 ~ 1 nM) versus COX­-2 (IC50 > 1 µM), and a logD value of 4.26. Brain uptake of radioactivity after [C-11]PS13 injection was high (4.4 SUV) and reversible. PS13 and KTPMe decreased brain uptake of radioactivity, but also increased the plasma concentration of radioligand. Compartmental modeling showed that VT was reduced 70% by PS13 and 60% by KTPMe, revealing a high COX-1 specific signal in baseline experiments. In the context of using [C-11]PS13 to detect neuroinflammation, we noted higher radioactivity uptake in the side ipsilateral to drug treatment than in the untreated contralateral side. This higher uptake was acute and absent by day 3.Conclusions [C-11]PS13 is a promising PET radioligand for measuring brain microglial COX-1, both as a biomarker of neuroinflammation and as a potential target for therapy with NSAIDs. $$graphic_C1408AF6-CC63-493C-9FEE-18D906CD32CC$$ $$graphic_72AE5283-E065-43BF-9548-FA304DE90469$$