TY - JOUR T1 - Chemical studies aimed at developing improved PET radioligands for imaging brain cyclooxygenase-2 JF - Journal of Nuclear Medicine JO - J Nucl Med SP - 1448 LP - 1448 VL - 62 IS - supplement 1 AU - Somachukwu Umeozulu AU - Nicholas Young AU - Carlotta Taddei AU - Fabrice Simeon AU - Victor Pike Y1 - 2021/05/01 UR - http://jnm.snmjournals.org/content/62/supplement_1/1448.abstract N2 - 1448Background: Positron emission tomography (PET) is a sensitive technique that relies on radiotracers tagged with short-lived positron emitters, usually carbon-11 (t1/2=20 min) or fluorine-18 (t1/2=110 min), to image molecular processes and structures in the human body. Neuroinflammation is now strongly implicated in the progression of major neuropsychiatric disorders, such as clinical depression and dementia caused by Alzheimer’s disease. Cyclooxygenase-2 (COX-2) is a key enzyme for promoting neuroinflammation. Ability to quantify COX-2 expression in human brain with PET would be valuable for biomedical research and for drug development to treat these disorders. [11C]3-(4-Methylsulfonylphenyl)-4-phenyl-5-trifluoromethyl isoxazole ([11C]TMI; [11C]1; Scheme)1 is a promising COX-2 PET radioligand in monkey but requires further detailed study and characterization. Potentially, the trifluoromethyl (CF3) group in TMI can be labeled with carbon-11 or fluorine-18 with the copper(I) derivative of either [11C]fluoroform2 or [18F]fluoroform3 as a labeling agent. Our aim is to use these labeling agents to prepare [11C]TMI and [18F]TMI for detailed evaluation as COX-2 radioligands. Methods: From the literature, we explored two methods based on [3+2] cycloaddition reactions between an in situ generated nitrile oxide and an alkyne to produce either a 5-tributyltin (4) or 5-pinacolborane isoxazole (8) precursor for radiolabeling. These methods were: 1) treatment of a benzimidoyl chloride (2) with a SnBu3-substituted alkyne (3); and 2) treatment of 2 with phenylacetylene (6) in the presence of the ruthenium catalyst [Cp*Ru(cod)Cl]4, followed by functionalization into the tin or boronic precursor. Precursor produced from these methods would then be subjected to labeling with [11C]CuCF3 or [18F]CuCF3 in order to produce [11C]TMI or [18F]TMI, respectively (Scheme). Results: Detailed NMR spectroscopy of the product made via Method 1 revealed that compound 5 was generated as an unexpected isomer of the desired precursor 4. Nonetheless, 5 was amenable to labeling by treatment with the copper(I) derivatives of [11C]fluoroform2 and [18F]fluoroform3 thus forming the labeled isomer of TMI in greater than 14% isolated yield, as determined by radio-HPLC analysis of crude product. For Method 2, the formation of the isoxazole 7 in the presence of ruthenium catalyst was successful (84% yield). Attempts to attach the tributyltin or pinacolborane group are in progress. Conclusions: Successful labeling of 5 indicates that the requisite isomer 4 should be amenable to direct labeling under the proposed methods to produce [11C]TMI or [18F]TMI. The chemistry of labeling simple model isoxazoles with [11C]CuCF3 or [18F]CuCF3 is also being explored to support deeper understanding of the new radiochemical method. Acknowledgements: This work was supported by the Intramural Research Program of NIH (National Institute of Mental Health). References: 1. Kumar JSD et al., Bioorg Med Chem Lett 2018, 28 (23-24), 3592-3595. 2. Haskali MB and Pike VW., Chemistry 2017, 23 (34), 8156-8160. 3. Yang BY et al., Scientific Reports 2019, 9 (1), 14835. 4. Grecian S and Fokin VV., Angew Chem Int Ed Engl 2008, 47 (43), 8285-7. ER -