Para-hydrogen labeled agents and their use in magnetic resonance imaging

Abstract

The invention provides a method of magnetic resonance investigation of a sample, said method comprising: (i) reacting para-hydrogen enriched hydrogen with a hydrogenatable MR imaging agent precursor containing a non-hydrogen non-zero nuclear spin nucleus to produce a hydrogenated MR imaging agent; (ii) administering said hydrogenated MR imaging agent to said sample; (iii) exposing said sample to radiation of a frequency selected to excite nuclear spin transitions of said non-zero nuclear spin nucleus in said hydrogenated MR imaging agent; (v) detecting magnetic resonance signals of said non-zero nuclear spin nucleus from said sample; and (vi) optionally, generating an image or biological functional data or dynamic flow data from said detected signals.

1 . A method of magnetic resonance investigation of a sample, said method comprising: 
 (i) reacting para-hydrogen enriched hydrogen with a hydrogenatable MR imaging agent precursor containing a non-hydrogen non zero nuclear spin nucleus to produce a hydrogenated MR imaging agent;    (ii) administering said hydrogenated MR imaging agent to said sample;    (iii) exposing said sample to radiation of a frequency selected to excite nuclear spin transitions of said non-zero nuclear spin nucleus in said hydrogenated MR imaging agent;    (v) detecting magnetic resonance signals of said non-zero nuclear spin nucleus from said sample; and    (vi) optionally, generating an image or biological functional data or dynamic flow data from said detected signals.    
     
     
         2 . A method as claimed in  claim 1  wherein said enriched hydrogen has a more than 45% proportion of para-hydrogen.  
     
     
         3 . A method as claimed in  claim 1  wherein said enriched hydrogen has a more than 90° proprtion of para-hydrogen.  
     
     
         4 . A method as claimed in any of the preceding claims wherein said MR imaging agent precursor contains nuclei selected from F, Li, C, N, Si and P nuclei.  
     
     
         5 . A method as claimed in  claim 4  wherein said non-zero nuclear spin nucleus is selected from  13 C,  15 N and  29 Si.  
     
     
         6 . A method as claimed in  claim 5  wherein said non-zero nuclear spin nucleus is  13 C.  
     
     
         7 . A method as claimed in any one of  claims 1  to  6  wherein said non-zero nuclear spin nucleus is present at a level greater than its natural isotopic abundance.  
     
     
         8 . A method as claimed in any one of  claims 1  to  7  wherein said precursor contains a hydrogenatable unsaturated carbon-carbon bond.  
     
     
         9 . A method as claimed in  claim 8  wherein said non-zero nuclear spin nucleus is present in said precursor one or two bonds distant from said unsaturated bond.  
     
     
         10 . A method as claimed in  claim 9  wherein said nucleus one or two bonds distant from said unsaturated bond is only directly bonded to atoms which in their predominant isotopic state have zero nuclear spin.  
     
     
         11 . A method as claimed in any one of  claims 1  to  10  wherein in said MR imaging agent the coupling constant (J) between said non-zero spin nucleus and a proton deriving from para-hydrogen is between 10 and 100 Hz.  
     
     
         12 . A method as claimed in  claim 11  wherein the nmr signal from said non-zero nuclear spin nucleus in said MR imaging agent has a line width of less than 10 Hz.  
     
     
         13 . A method as claimed in  claim 12  wherein said MR imaging agent has a molecular weight of less than 500D.  
     
     
         14 . A method as claimed in any one of  claims 1  to  13  wherein said MR imaging agent is water-soluble.  
     
     
         15 . A method as claimed in any one of  claims 1  to  14  wherein the chemical shift and/or the coupling constant of said non-zero nuclear spin nucleus in said MR imaging agent is sensitive to the physicochemical environment of said agent.  
     
     
         16 . A method as claimed in  claim 15  wherein said non-zero nuclear spin nucleus in said MR imaging agent is sensitive to pH and wherein said signals are manipulated to produce an image or data indicative of pH.  
     
     
         17 . A method as claimed in any one of  claims 1  to  16  wherein step (i) is effected in a magnetic field smaller than the earth's ambient field.  
     
     
         18 . A method as claimed in  claim 17  wherein step (i) is effected in a magnetic field of less than 10 μT.  
     
     
         19 . A method as claimed in any one of  claims 1  to  18  wherein in steps (iii) and (iv) said sample is exposed to a 90° pulse of radiation of a frequency selected to excite nuclear spin transitions of said non-zero nuclear spin nucleus followed by 180° pulses of said radiation, where the time interval between said 180° pulses is 2τ and the time interval between said 90° pulse and the subsequent 180° C. pulse is τ plus Δτ where Δτ is 1/(2J) where J is the coupling constant of said non-zero nuclear spin nucleus in said MR imaging agent.  
     
     
         20 . A method as claimed in any one of  claims 1  to  18  wherein in steps (iii) and (iv) said sample is exposed to a 90° pulse of radiation of a frequency selected to excite nuclear spin transitions of said non-zero nuclear spin nucleus followed at time intervals of 21 by 180° pulses of said radiation of the same phase and where for the first n said 180° pulses said sample is simultaneously exposed to 180° pulses of radiation of a frequency selected to excite proton nuclear spin transitions, the relation between n and τ being τ=1/(4nJ) where J is the coupling constant of said non-zero nuclear spin nucleus in said MR imaging agent.  
     
     
         21 . A method as claimed in any one of  claims 1  to  19  wherein step (i) is effected using a rhodium-based hydrogenation catalyst.  
     
     
         22 . Use of para-hydrogen enriched hydrogen in the manufacture of an MR imaging agent for non-proton MR imaging of a sample.  
     
     
         23 . Use of para-hydrogen enriched hydrogen in MR imaging of a sample.  
     
     
         24 . Use as claimed in either one of claims  22  and  23  wherein said imaging is  13 C NMR imaging of a sample.  
     
     
         25 . A precursor compound: 
 (i) containing a hydrogenatable unsaturated bond;    (ii) containing a non-hydrogen non zero nuclear spin nucleus at greater than natural isotopic abundance;    (iii) having a molecular weight below 1000OD; and    (iv) which following hydrogenation has an nmr spectrum for said non-hydrogen non zero nuclear spin nucleus which is a multiplet having a coupling constant relative to one of the hydrogens introduced by hydrogenation of 1 to 300 Hz and having a linewidth of less than 100 Hz,    and wherein when said precursor compound is a  13 C enriched compound then said nucleus is a quaternary carbon nucleus.    
     
     
         26 . A compound as claimed in  claim 25  containing the following molecular sub-units: 
 (i) at least one C═C or C≡C bonds;  
 (ii) a C, N or Si atom separated by one or two bonds from a C═C or C≡C bond, bound only to atoms the naturally most abundant isotope form of which has a nuclear spin I=0, and not coupled by a series of covalent bonds to any atoms the naturally most abundant isotopic form of which has I>½; and  
 (iii) at least one water-solubilizing moiety, ie. a functional group which imparts water solubility to the molecule.  
 
     
     
         27 . A reporter compound: 
 (i) containing at least two protons;    (ii) containing a non-hydrogen non zero nuclear spin nucleus at greater than natural isotopic abundance;    (iii) having a molecular weight below 1000D; and    (iv) having an nmr spectrum for said non-hydrogen non zero nuclear spin nucleus which is a multiplet having a coupling constant relative to one of said at least two protons 1 to 300 Hz and having a linewidth of less than 100 Hz,    and wherein when said reporter compound is a  13 C enriched compound then said nucleus is a quaternary carbon nucleus.    
     
     
         28 . A compound as claimed in  claim 27  containing the following molecular sub-units: 
 (i) at least one CH—CH or CH═CH moiety;  
 (ii) a C, N or Si atom separated by one or two bonds from a CH—CH or CH═CH moiety, bound only to atoms the naturally most abundant isotopic form of which has I=0, and not coupled by a series of covalent bounds to any atoms the naturally most abundant isotopic form of which has I>½; and  
 (iii) at least one water-solubilizing moiety, ie. a functional group which imparts water solubility to the molecule.  
 
     
     
         29 . A physiologically tolerable MR imaging agent composition comprising an MR imaging agent together with one or more physiologically tolerable carriers or excipients, said imaging agent containing non-hydrogen nuclei having a nuclear spin of ½, characterised in that said nuclei are polarized such that their nmr signal intensity is equivalent to a signal intensity achievable in a magnetic field of at least 0.1T.  
     
     
         30 . A composition as claimed in  claim 29  wherein said nuclei are polarized such that their nmr signal intensity is equivalent to a signal intensity achievable in a magnetic field of at least 100T.  
     
     
         31 . A composition as claimed in either one of claims  29  and  30  wherein said nucleus is present in an amount in excess of its natural isotopic abundance.  
     
     
         32 . A composition as claimed in  claim 31  wherein said nucleus is present in a selected position in the molecular structure of said agent at an abundance of at least 50%.  
     
     
         33 . A composition as claimed in any one of  claims 29  to  32  wherein T 1  for said nuclei at earth's magnetic field and at ambient temperature is at least 1 second.  
     
     
         34 . An apparatus for hydrogenation comprising: 
 a reaction chamber having therein a reaction zone, said reaction chamber having a gas inlet and a gas outlet;    a temperature controller arranged to control the temperature in said reaction zone; and    magnetic shielding arranged about said reaction zone and sufficient to cause the magnetic field in said reaction zone to be less than 10 μT.    
     
     
         35 . Apparatus as claimed in  claim 34  wherein said reaction zone contains a particulate bed and said reaction chamber is provided with a liquid outlet below said bed and a liquid inlet above said bed.  
     
     
         36 . Apparatus as claimed in  claim 35  comprising: 
 (i) a reservoir of para-hydrogen enriched hydrogen;  
 (ii) a reaction chamber having a reaction zone containing a particulate bed and having a first gas inlet below said bed, a first gas outlet above said bed, a solution inlet above said bed and a solution outlet below said bed;  
 (iii)  
 a gas conduit from said reservoir to said first gas inlet in the reaction chamber;  
 (iv) a temperature controller disposed around said reaction chamber at at least said reaction zone; and  
 (v) a magnetic shield disposed around said reaction chamber at at least said reaction zone.  
 
     
     
         37 . The use of para-hydrogen enriched hydrogen in the manufacture of an MR imaging agent for use in a method of diagnosis involving generation of an MR image by non-proton MR imaging.  
     
     
         38 . The use of a hydrogenatable compound containing a non hydrogen non zero nuclear spin nucleus in the manufacture of an MR imaging agent for use in a method of diagnosis involving generation of an MR image by non-proton MR imaging, said manufacture involving hydrogenation of said compound with para-hydrogen enriched hydrogen.