Synthesis of [¹⁸F]PS13 and Evaluation as a PET Radioligand for Cyclooxygenase-1 in Monkey

Abstract

Cyclooxygenase-1 (COX-1) and its isozyme COX-2 are key enzymes in the syntheses of prostanoids. Imaging of COX-1 and COX-2 selective radioligands with positron emission tomography (PET) may clarify how these enzymes are involved in inflammatory conditions and assist in the discovery of improved anti-inflammatory drugs. We have previously labeled the selective high-affinity COX-1 ligand, 1,5-bis­(4-methoxyphenyl)-3-(2,2,2-trifluoroethoxy)-1H-1,2,4-triazole (PS13), with carbon-11 (t 1/2 = 20.4 min). This radioligand ([11C]­PS13) has been successful for PET imaging of COX-1 in monkey and human brain and in periphery. [11C]­PS13 is being used in clinical investigations. Alternative labeling of PS13 with fluorine-18 (t 1/2 = 109.8 min) is desirable to provide a longer-lived radioligand in high activity that might be readily distributed among imaging centers. However, labeling of PS13 in its 1,1,1-trifluoroethoxy group is a radiochemical challenge. Here we assess two labeling approaches based on nucleophilic addition of cyclotron-produced [18F]­fluoride ion to gem-difluorovinyl precursors, either to label PS13 in one step or to produce [18F]­2,2,2-trifluoroethyl p-toluenesulfonate for labeling a hydroxyl precursor. From the latter two-step approach, we obtained [18F]­PS13 ready for intravenous injection in a decay-corrected radiochemical yield of 7.9% and with a molar activity of up to 7.9 GBq/μmol. PET imaging of monkey brain with [18F]­PS13 shows that this radioligand can specifically image and quantify COX-1 without radiodefluorination but with some radioactivity uptake in skull, ascribed to red bone marrow. The development of a new procedure for labeling PS13 with fluorine-18 at a higher molar activity is, however, desirable to suppress occupancy of COX-1 by carrier at baseline.

Is cyclooxygenase‐1 involved in neuroinflammation?

“…Because of the short half‐life of carbon‐11 (20.4 min), 11 C‐labeled tracers cannot be distributed to remote imaging centers. After the promising results acquired with [ 11 C]PS13, the same group thus attempted to radiolabel PS13 with 18 F (half‐life 109.8 min) (Taddei et al., 2021). The resulting [ 18 F]PS13 was used to make two brain scans (at baseline and after pretreatment with unlabeled PS13) in two rhesus monkeys and a single whole‐body scan in one monkey.…”

Fluorine-18 Labelled Radioligands for PET Imaging of Cyclooxygenase-2

“…There has also been significant progress in the development of COX-2-targeting radioligands for imaging inflammation, cancer, and neurological disorders [54][55][56][57]. Over the last decades, a variety of radionuclide-based imaging agents have been developed by the incorporation of radioisotopes such as 11 C, 18 F, 99m Tc, 123 I, and 125 I into NSAIDs and related compounds [55,56,[58][59][60][61][62][63][64][65][66][67][68][69][70][71]. Selected examples of PET radioligands for COX-2 imaging are presented in Figure 3 Molecules 2022, 27, x FOR PEER REVIEW 3 of 20…”

“…There has also been significant progress in the development of COX-2-targeting radioligands for imaging inflammation, cancer, and neurological disorders [54][55][56][57]. Over the last decades, a variety of radionuclide-based imaging agents have been developed by the incorporation of radioisotopes such as 11 C, 18 F, 99m Tc, 123 I, and 125 I into NSAIDs and related compounds [55,56,[58][59][60][61][62][63][64][65][66][67][68][69][70][71]. Selected examples of PET radioligands for COX-2 imaging are presented in Figure 3 A major focus involves 18 F-labeled radioligands, due to their favourable half-life (t1/2 = 109.8 min), ease of production, the availability of a variety of radiofluorination methods, and better imaging characteristics of the short-lived positron emitter 18 F. This review article primarily covers 18 F-labeled radioligands reported in the last decade for targeting COX-2.…”

Towards PET imaging of the dynamic phenotypes of microglia

“…Nevertheless, [ 11 C]PS13 was evaluated in healthy humans, showing good test–retest reliability, and thus it would be interesting to investigate binding differences between healthy subjects and, for example, AD patients [ 129 ]. To provide a radiotracer with a longer half‐life, a [ 18 F]PS13 was developed, showing similar promising results in non‐human primates, however, optimization of the radiolabeling procedure is required to obtain [ 18 F]PS13 with sufficient molar activity [ 130 ]. [ 11 C]MC1 was evaluated in two healthy volunteers and two patients with rheumatoid arthritis as a proof of principle, and notably higher binding in inflamed joints was observed in patients versus controls [ 127 ].…”