Syntheses of [11C]2- and [11C]3-trifluoromethyl-4-aminopyridine: potential PET radioligands for imaging demyelinating diseases

619 Objectives: Trifluoromethyl groups are of great interest in radiopharmaceuticals as they can enhance chemical and metabolic stability and allow for the manipulation of physicochemical properties such as pKa, lipophilicity and bioavailability1 while providing a handle that is amenable to labeling with carbon-112 or fluorine-183-7. Although most available methods are focused on 18F-labeling with [18F]fluoroformor its copper(I) derivative, the main limitation for PET radiotracer development lies in the low to moderate molar activities achievable by these methods. To address this problem, the synthesis of [11C]fluoroform from cyclotron-produced [11C]methane was recently developed, allowing for the retention of high molar activity and the labeling of small molecules with [11C]trifluoromethyl groups with molar activities exceeding 5.4 Ci/μmol2. Aminopyridines are of interest for the development of PET radiotracers. For example, radiolabeled derivatives of 4-aminopyridine (4AP), an FDA-approved drug for multiple sclerosis that binds to voltage-gated K+ channels present in demyelinated axons, have been proposed for PET imaging of demyelinating diseases. Here, we describe methods for producing [11C]trifluoromethyl derivatives of 4AP and present the first imaging results with [11C]3-trifluoromethyl-4-aminopyridine ([11C]3-CF3‑4AP) in a Rhesus macaque. Methods: The [11C]fluoroform production method2 was adapted to generate [11C]methane from cyclotron-produced [11C]carbon dioxide using a GE Tracerlab FX MeI synthesizer. Subsequently, [11C]methane was converted into [11C]fluoroform by passing it through a heated reactor containing CoF3. This was then converted into the trifluoromethylating agent [11C]CuCF3 for the systematic investigation of its use to produce [11C]CF3-4AP derivatives from pyridines donning a halide group (iodo or bromo) at 2- or 3-position and an ester, amide or amine group at the 4-position. Finally, [11C]3-CF3-4AP was produced for preliminary imaging in a healthy Rhesus macaque. Dynamic PET data was acquired for 120 min after a slow bolus injection of 1.93 mCi of [11C]3-CF3‑4AP. Results: Production of [11C]CHF3 compared well to previous reports. While the overall radiochemical yield from [11C]carbon dioxide, 52 ± 8% (n=15), was comparable to that from [11C]methane, changes to the gas flow to increase pressure and contact time between [11C]methane and CoF3 further improved the radiochemical purity of the [11C]fluoroform from about 80% to 94 ± 4% (n=15). Trifluoromethylation of bromo- and iodopyridine substrates containing electron-withdrawing (CO2Me) and electron-donating groups (NHBoc and NH2) with [11C]fluoroform resulted in a wide range of yields (5-97%), with iodo-precursors giving higher yields than their bromo counterparts. Dynamic PET imaging of [11C]3-CF3-4AP showed a fast high uptake of radioactivity in brain followed by a fast washout, similar to that reported for [18F]3-F-4AP8. Conclusions: This work illustrates the versatility of labeling pyridines with [11C]fluoroform and provides initial evidence for the potential use of [11C]3-CF3‑4AP as a PET radioligand for demyelination. References:1Purser S, Moore PR, Swallow S, et al.Chem Soc Rev37, 320-330. 2Haskali MB, Pike VW. ChemEur J23, 8156-8160. 3Huiban M, Tredwell M, Mizuta S, et al.Nat Chem5, 941-944. 4van der Born D, Sewing C, Herscheid JK, et al.Angew Chem Int Ed Engl53, 11046-11050. 5Ruhl T, Rafique W, Lien VT, et al.Chem Commun (Camb)50, 6056-6059. 6Ivashkin P, Lemmonier G, Cousin J, et al.Chemistry20, 9514-9518. 7Carroll L, Evans HL, Spivey AC, et al.Chem Commun (Camb)51, 8439-8441. 8Brugarolas P, Sanchez-Rodriguez JE, Tsai HM, et al.Sci Rep8, 607.