Microfluidic radiosynthesis of a radiolabeled compound using electrochemical trapping and release

Abstract

Methods and apparatus enable radiosynthesis of radiolabeled compounds using electrochemical trapping and release. The trapping and release of radioactive isotopes all occur inside a microreactor, a vial or similar device, thus eliminating the need for azeotropic drying and several dead-end filling steps, as well as the necessity to move concentrated radioisotopes from one compartment of the chip to another. These and other features allow radioisotope enrichment to be carried out internally within a radiochemical synthesis chip, providing faster and more robust operation, as well as producing very high radiochemical labeling yields.

1 . A method for the synthesis of a radiolabeled compound comprising a radioactive isotope using a microfluidic device, the method comprising:
 introducing a composition comprising a radioactive isotope to the microfluidic device;   electrochemically trapping the radioactive isotope using an electrode;   adding a composition comprising a reactant to the reactor;   electrochemically releasing the radioactive isotope from the electrode; and   contacting the reactant with the radioactive isotope to form the radiolabeled compound.   
   
   
       2 . The method of  claim 1 , wherein the radioactive isotope is F-18. 
   
   
       3 . The method of  claim 1 , wherein the reactant comprises mannose triflate. 
   
   
       4 . The method of  claim 3 , wherein the reactant is N-dimethoxytrityl-5′-O-dimethoxytrityl-3′-O-nosyl-thymidine and the radiolabeled compound is FLT. 
   
   
       5 . The method of  claim 2 , wherein a step of blowing an inert gas and a heating of the reactor is performed to dry the trapped F-18 before adding the composition comprising the reactant to the reactor. 
   
   
       6 . The method of  claim 1 , wherein the reactor is a coin-shaped reactor in a radio-synthesis chip. 
   
   
       7 . The method of  claim 1 , wherein the trapping and releasing is carried out by one or more electrodes. 
   
   
       8 . The method of  claim 7 , wherein the electrodes are located in or on at least one of a floor, a ceiling, and a side of the reactor or combinations thereof. 
   
   
       9 . The method of  claim 7 , wherein the electrodes are located in a channel in fluid communication with the reactor. 
   
   
       10 . The method of  claim 7 , wherein the electrodes are non-metal electrodes. 
   
   
       11 . The method of  claim 7 , wherein the electrodes are made of a material selected from the group consisting of a graphite, a composite graphite, and silicon and combinations thereof. 
   
   
       12 . The method of  claim 11 , wherein the electrodes are graphite polymer electrodes. 
   
   
       13 . The method of  claim 12 , wherein the polymer is selected from the group consisting of a DCPD, a polyethylene, and a glass. 
   
   
       14 . The method of  claim 7 , where the electrodes are metal electrodes. 
   
   
       15 . The method of  claim 14 , wherein the electrodes are covered with a protective coating. 
   
   
       16 . The method of  claim 1 , wherein at least one of the electrochemical trapping and the releasing is carried out in accordance with an on-chip feature. 
   
   
       17 . The method of  claim 1 , wherein at least one of the electrochemical trapping and the releasing is carried out in accordance with an in-reactor feature. 
   
   
       18 . The method of  claim 1 , wherein the trapping, the releasing and the radiolabeled compound formation are carried out within the same microreactor. 
   
   
       19 . The method of  claim 1 , wherein a radiochemical labeling yield of at least 55% is produced. 
   
   
       20 . The method of  claim 19 , wherein the yield is 55%, 65%, 75%, 85%, 95% or 99%. 
   
   
       21 . The method of  claim 1 , wherein the radioactive isotope is released into a non-aqueous solution. 
   
   
       22 . The method of  claim 21 , wherein the non-aqueous solution is an organic solution. 
   
   
       23 . The method of  claim 1 , wherein the reaction to form the radiolabeled compound is a substitution reaction. 
   
   
       24 . The method of  claim 23 , wherein the releasing is carried out simultaneously with the substitution reaction. 
   
   
       25 . The method of  claim 1 , wherein the reactant is in a solvent. 
   
   
       26 . The method of  claim 1 , wherein the electrochemical trapping is carried out in one or more passes. 
   
   
       27 . The method of  claim 1 , wherein the electrochemical releasing is carried out in accordance with one or more reversals of a voltage bias. 
   
   
       28 . A method for the synthesis of a radiolabeled compound using a microfluidic trap-release device, the method comprising:
 introducing a composition comprising a radioactive isotope to the device;   electrochemically trapping of the radioactive isotope;   adding a composition comprising a reactant to the device; and   electrochemically releasing the radioactive isotope into the trap-release device.   
   
   
       29 . The method of  claim 28 , wherein the trap-release device is a radiochemical microreactor. 
   
   
       30 . A microfluidic radiosynthesis apparatus, comprising:
 a first electrode configured to electrochemically trap a radioactive isotope;   a chamber; and   a second electrode configured to electrochemically release the radioactive isotope into the chamber.   
   
   
       31 . The apparatus of  claim 30 , wherein the apparatus is further configured for preparing a radiolabeled compound by performing a reaction of a reactant with the radioactive isotope. 
   
   
       32 . The apparatus of  claim 30 , wherein the radioactive isotope is F-18. 
   
   
       33 . The apparatus of  claim 30 , wherein the chamber is filled with a composition comprising a reactant. 
   
   
       34 . The apparatus of  claim 33 , wherein the reactant comprises mannose triflate. 
   
   
       35 . The apparatus of  claim 34 , wherein the reactant is N-dimethoxytrityl-5′-O-dimethoxytrityl-3′-O-nosyl-thymidine and the radiolabeled compound is FLT. 
   
   
       36 . The apparatus of  claim 33 , further configured to blow an inert gas and heat the chamber before adding the composition comprising the reactant. 
   
   
       37 . The apparatus of  claim 30 , wherein the chamber is part of a coin-shaped reactor in a radio-synthesis chip. 
   
   
       38 . The apparatus of  claim 30 , wherein the electrodes are located in or on at least one of a floor, a ceiling, and a side of the chamber or combinations thereof. 
   
   
       39 . The apparatus of  claim 30 , wherein the electrodes are located in a channel in fluid communication with the chamber. 
   
   
       40 . The apparatus of  claim 30 , wherein the electrodes are non-metal electrodes. 
   
   
       41 . The apparatus of  claim 30 , wherein the electrodes are made of a material selected from the group consisting of graphite, a composite graphite, and silicon and combinations thereof. 
   
   
       42 . The apparatus of  claim 41 , wherein the electrodes are graphite polymer electrodes. 
   
   
       43 . The apparatus of  claim 42 , wherein the polymer is selected from the group consisting of a DCPD, a polyethylene and a glass. 
   
   
       44 . The apparatus of  claim 30 , where the electrodes are metal electrodes. 
   
   
       45 . The apparatus of  claim 44 , wherein the electrodes are covered with a protective coating. 
   
   
       46 . The apparatus of  claim 30 , wherein at least one of the first and the second electrodes is configured as an on-chip feature or as an in-reactor feature. 
   
   
       47 . The apparatus of  claim 30 , wherein the electrochemical trapping is carried out in one or more passes. 
   
   
       48 . The apparatus of  claim 30 , wherein the electrochemical releasing is carried out in accordance with one or more reversals of a voltage bias.