Electrochemical [11C]CO2 to [11C]CO conversion for PET imaging

Development of a novel electrochemical radiochemistry methodology i.e. reduction of [11C]CO2 to [11C]CO at room temperature and pressure using metal cyclam complexes.


General method and materials
All chemicals and dry solvents were purchased from Sigma-Aldrich and Alfa Aesar and used as received. HPLC analysis was performed on an Agilent 1200 system equipped with a UV detector (λ=254 nm) and a β+-flow detector coupled in series. A reverse-phase column (Agilent Eclipse XDB-C18, 4.6 x 150 mm, 5 μm) was used with a flow rate of 1 mL min -1 . The gradient for 5 was linear between 10-90% over 5 min (CH 3 CN:0.1 M NH 4 HCO 2 , 10:90), isocratic in between 5-9 min (CH 3 CN:0.1 M NH 4 HCO 2 , 90:10) and linear in between 9-13 min (CH 3 CN:0.1 M NH 4 HCO 2 , 90:10). Identification of all radioactive products was confirmed by co-elution with the corresponding non-radioactive compounds. The reference compound 5 elutes at RT = 5.6 min. 1 H NMR spectra were obtained using a BRUKER AVANCE Electronic Supplementary Material (ESI) for ChemComm. This journal is © The Royal Society of Chemistry 2017 AV 400 MHz spectrometer. Mass spectrometry was performed using on a Water LCT premier ES-TOF. Controlled-potential electrolysis (CPE) was carried out in a three-necked flask with a three-electrode set-up using carbon paper as working electrode and Pt grid counter electrode with a Ag/AgCl/KCl(sat) reference electrode. The Faradaic yield was calculated from the amount of CO or H 2 accumulated in the headspace (60 mL), as measured by GC (Perkin-Elmer Clarus 580) fitted with a dual-ionisation detector (DID) connected to (molecular sieve column) to detect H 2 , CO, O 2 , CH 4 and N 2 and flame ionization detector (FID) connected to 1/8" SF x 5' Unibeads column to detect hydrocarbons. Helium was used as the GC carrier gas. Ignacio Garcia at Imperial recorded all XP spectra using a K-alpha + XPS spectrometer equipped with a MXR3 Al Kα monochromated X-ray source (h = 1486.6 eV). X-ray gun power was set to 72 W (6 mA and 12 kV). With this X-ray settings, the intensity of the Ag 3d 5/2 photoemission peak for an atomically clean Ag sample, recorded at 20 eV pass energy (PE), was 5 × 10 6 counts s -1 and the full width at half maximum (FWHM) was 0.58 eV. Binding energy calibration was made using Au 4f 7/2 (84.01 eV), Ag 3d 5/2 (368.20 eV) and Cu 2p 3/2 (932.55 eV). The pressure during the measurement of XP spectra was ≤ 1  10 -8 mbar. All XP spectra were charge corrected by referencing the fitted contribution of C-C graphitic-like carbon in the C 1s signal to 285 eV. [ 11 C]CO 2 was produced using a Siemens RDS112 cyclotron by the 11 MeV proton bombardment of nitrogen (+ 1% O 2 ) gas via the 14 N(p,α) 11 C reaction in an aluminium target with HAVAR front foil which was helium cooled on the front face. All source gasses were 9.9999% purity (BOC N6) and were used as received. The cyclotronproduced [ 11 C]CO 2 was bubbled in a stream of helium gas with a flow rate of 50 mLmin -1 post target depressurisation. The molar radioactivity of [ 11 C]5 (for entry 2 in Table 2) was estimated to be 56 GBq mol -1 (n=1).

Synthesis of 1 1
Nickel(II) chloride hexahydrate (0.29 g, 2.2 mmol, 1.8 eq.) was dissolved in warm ethanol (20 mL) and was added to a solution of cyclam (0.25 g, 1.2 mmol, 1 eq.) in ethanol (10 mL). The resulting light brown solution was stirred at 40 °C for 20 min. Diethyl ether (30 mL) was added to precipitate the product which was filtered and washed with diethyl ether (3 x 10 mL). This product was recrystallized by adding ether to a saturated solution of the product in methanol to yield pure product as a lilac solid

Synthesis of 2 2
Cyclen (1.0 g, 5.8 mmol, 1 eq.) was dissolved in ethanol (10 mL) in a scintillation vial equipped with a stirrer bar. The colourless solution was heated and stirred at 65 °C using an oil bath. Zn(ClO 4 ) 2 ·6H 2 O (2.6 g, 7.0 mmol , 1.2 eq.) was dissolved in ethanol (3 mL), and this colourless solution was slowly added to the ligand at 65 °C dropwise. Upon zinc addition, the colourless mixture became turbid and a white precipitate formed.

Non-radioactive controlled potential electrolysis experiments on 1 and 2
Controlled-potential electrolysis (CPE) was carried out in a three-necked flask with a three-electrode set-up using carbon paper as working electrode and Pt grid counter electrode with a Ag/AgCl/KCl(sat) reference electrode. The Faradaic yield was calculated from the amount of CO or H 2 accumulated in the headspace (60 mL), as measured by GC (Perkin-Elmer Clarus 580) fitted with a dual-ionisation detector (DID) connected to (molecular sieve column) to detect H 2 , CO, O 2 , CH 4 and N 2 and flame ionization detector (FID) connected to 1/8" SF x 5' Unibeads column to detect hydrocarbons. Helium was used as the GC carrier gas. In non-radioactive electrolysis experiments with both catalyst 1 and 2 at -1.8 V the GC detector became saturated and so -1.4 and -1.6 V were used. In radiochemical experiments it was decided that -1.8 V would give better [ 11 C]CO production.  Figure S4 shows that the characteristic band of ZnO can be clearly seen with a peak at 988 eV and shoulder at 990 eV.

Radiochemistry vial A preparation
The screen printed electrodes (DRP-C110) were provided by DropSens. The electrode connector was made in-house. This was done by taking a 3-way 1-row housing (yellow box) (RS components, Stock No. 360-6061). The 3-way housing had connector pins in line with the 3 connectors on the electrode and a good electrical connection was maintained by cutting a 0.5 mm slit in the connector (same width as the electrode). Each connector pin was individually connected to the potentiostat (Ivium CompactStat). The 3-way connector sits at the top of the reaction vessels and the wires pass through the silicone washer to maintain an airtight seal. The electrolysis vial (Fig 1.A