Methods to prepare carbon-isotope labeled organohalides with high specific radioactivity from carbon-isotope monoxide
Methods and reagents for labeling synthesis of organohalides by transition metal mediated carbonylation reactions using carbon-isotope labeled carbon monoxide are provided. The resultant carbon-isotope labeled organohalides are useful as radiopharmaceuticals, especially for use as precursors in Positron Emission Tomography (PET). Associated PET tracers and kits for PET studies are also provided.
1. A method for labeling synthesis of organohalides, comprising:
(a) providing a high pressure reaction chamber having a liquid/gas inlet and a gas inlet in a bottom surface thereof,
(b) providing a substrate solution to be labeled mixed with a transition metal complex,
(c) providing H 2 gas or HOR, with optional water, where R is independently linear or lower cyclic alkyl or aryl,
(d) introducing a carbon-isotope monoxide enriched gas-mixture into the reaction chamber via the gas inlet,
(e) introducing at high-pressure said H 2 gas or HOR, with optional water, into the reaction chamber via the liquid/gas inlet,
(f) introducing at high-pressure said substrate solution mixed with transition metal complex into the reaction chamber via the liquid/gas inlet,
(g) waiting a predetermined time while the labeling synthesis occur, and
(h) removing the labeled compounds from the reaction chamber,
(i) reducing the labeled compounds to alcohol,
(j) substituting with a halogen atom to obtain the labeled organohalides.
2. A method of claim 1 , wherein the carbon-isotope monoxide enriched gas-mixture is produced by a method comprising:
(a) providing carbon-isotope dioxide in a suitable carrier gas,
(b) converting carbon-isotope dioxide to carbon-isotope monoxide by introducing said gas mixture in a reactor device,
(c) trapping carbon-isotope monoxide in a carbon monoxide trapping device, wherein carbon-isotope monoxide is trapped but not said carrier gas, and
(d) releasing said trapped carbon-isotope monoxide from said trapping device in a well defined micro-plug, whereby a volume of carbon-isotope monoxide enriched gas-mixture is achieved.
3. A method of claim 1 , wherein the carbon-isotope is 11 C, 13 C, or 14 C.
4. A method of claim 1 , wherein the carbon-isotope is 11 C.
5. A method of claim 1 , wherein the step of introducing the substrate solution mixed with a transitional metal complex is performed using a pressure that is about 80 times higher than the pressure before the introduction, in order to maintain a pseudo one-phase system.
6. A method of claim 1 , wherein the step of waiting a predetermined time comprises adjusting the temperature of the reaction chamber to enhance the labeling synthesis.
7. A method of claim 1 , wherein the transitional metal complex is selected from a group of transition metal complex comprising Pd, Rh, Co, Pt or Ru.
8. A method of claim 1 , wherein the substrate is alkyl- or aromatic halide or triflate, olefin or acetylene.
9. A method of claim 8 , wherein the substrate is alkyl- or aromatic halide or triflate having the formula of R′ 1 —X′, wherein R′ 1 is defined as independently linear or cyclic lower alkyl or substituted aryl with Cl, F or —OR, and X′ is I, Br or OTf.
10. Labeled organohalides generated according to a method of claim 9 having the formula of
wherein R′ 1 is defined as independently linear or cyclic lower alkyl or substituted aryl with Cl, F or —OR, X′ is I, Br or OTf, X is I or Br.
11. A method of claim 8 , wherein the substrate is olefin having the formula of
wherein R 1 is defined as independently linear or cyclic lower alkyl or aryl.
12. A method of claim 8 , wherein the substrate is acetylene having the formula of
wherein R 1 is defined as independently linear or cyclic lower alkyl or aryl.
13. A method of claim 12 , wherein only water is used in step (c).