Title of Invention

PROCESS FOR THE PREPARATION OF AN MR CONTRAST AGENT

Abstract The present invention provides a process for the preparation of an MR contrast agent, said process comprising: i) obtaining a solution in a solvent of a hydrogenatable, unsaturated substrate compound and a catalyst for the hydrogenation of said substrate compound; ii) introducing said solution in droplet form into a chamber containing hydrogen gas (H¿2?) enriched in para-hydrogen (p-?1¿H¿2?) and/or ortho-deuterium (o-?2¿H¿2?) whereby to hydrogenate said substrate to form a hydrogenated imaging agent; iii) optionally subjecting said hydrogenated imaging agent to a magnetic field having a field strength below earth"s ambient field strength; iv) optionally dissolving said imaging agent in an aqueous medium; v) optionally separating said catalyst from the solution of said imaging agent in said aqueous medium; vi) optionally separating said solvent from the solution of said imaging agent in said aqueous medium; and vii) optionally freezing the solution of said imaging agent in said aqueous medium.
Full Text FORM 2
THE PATENTS ACT 1970
[39 OF 1970]
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
[See Section 10; rule 13]
"PROCESS FOR THE PREPARATION OF AN MR CONTRAST AGENT"
AMERSHAM HEALTH AS, a Norwegian company, Nycoveien 2, 0485 Oslo, Norway,
The following specification particularly describes the invention and the manner in which it is to be performed:

This invention relates to a process and apparatus for para-hydrogen or orthp-deuterium induced nuclear spin polarization of an Unsaturated compound, and more ^preferably for the preparation of a contrast agent for a magnetic resonance imaging procedure.
Hydrogen molecules H2) exist in two different forms, namely para-hydrogen where the nuclear spins are anti-parallel and out-of-{phase (the singlet state) and ortho-hydrogen where they are parallel or anti-parallel and in-phase (the triplet! state) . At room temperature, the two forms are in equilibrium with an approximately 1:3 ratio of para to ortho hydrogen. At 80K the ratio is about 48:52 and at 20l| it approaches 100:0 (actually about 99.8:0.2).
In contrast, deuterium (Da or 2H2), where the aH nucleus has a nuclear spin (S) of 1 rather than bi, exists in nine different [forms, three anti-symmetric para forms and six symmetric ortho forms. At ambient temperature, the ratio of ortho-deuterium (o-D2) to para-deuterium (p-D2) in an ortho-/para-deuterium mixture is about 2:1, at 60K it is a bout 3:1 and at 20K it is about 98:2. (Deuterium freezes fat about 19K) .
In W099/24080, which is hereby incorporated by reference, it is described how para-hydrogen may be used to catalytically hydrogenate unsaturated compounds, transferring to those compounds the anti-parallel proton spins of the para-hydrogen molecule, and transferring nuclear spin polarization from the para-hydrogen deriving protons to non-hydrogen non-aero nuclear spin (i.e. S*u) nuclei in the hydrogenated compound, e.g. "C or 15N- nuclei. In -this way, -such non-zrer spin_ nuclei may be given a nuclear spin polarization (hyperpDlarization) equivalent to that achieved in a kiloTesla or higher magnetic field. The nuclear


-2-

magnetic resonance signals emitted by such hyperpolarized
nuclei may be used for .magnetic resonance imaging in
much the same way as has (been done with hyperpolarized
3He-MRI.
A similar nuclear spin hyperpolarization may

likewise be achieved by hydrogenation with deuterium, more particularly with a-deuterium or with hydrogen {lH2) /deuterium(2H2) mixtures, particularly deuterium or hydrogen/deuterium mixtures in which the p/o ratio for hydrogen and the o/p ratip for deuterium are higher than the equilibrium values (l|:3 and 2:1) at ambient temperature, e.g. having ratios corresponding to the equilibrium values at temperatures below 8OK, more particularly temperatures! below 40K, especially between liquid helium UK) temperatures and 30K, more especially at temperatures between the melting points of the hydrogen and/or deuterium and 25K,
The hydrogenation and/or deuteration, e.g. of an unsaturated bond in a subgatrate molecule whereby to introduce a 2H or 2H atom pound to each of the atoms linked by the unsaturated! bond, serves to introduce a hydrogen/deuterium spin distribution into the hydrogenated substrate molecule which is other than the equilibrium distribution tat ambient temperature. Where the substrate molecule contains non-zero nuclear spin nuclei (in natural or a boW natural isotopic abundances) , particularly! where these non-zero spin (S*0) nuclei are close in! the molecular structure of the hydrogenated substrate td the lH or 2H atoms introduced by the hydrogenation, the; introduction lH or 1H gtome can induce a nuclear spin distribution in the S+0 nuclei which is other than the equilibrium distribution at ambient temperature. These non-equilibrium nuclear spin distributions for the introduced.protons/deuterons and for the S=Q nuclei in the! hydrogenated substrate may be harnessed to provide signfal enhancement in magnetic resonance imaging (MRI) techniques, including in vivo


MRI.
The term "hyperpolarization" is used herein to
denote a nuclear spin population distribution for a non-
zero nuclear spin imaging nucleus in a hydrogenated
substrate which is other[than the equilibrium population
distribution at ambient to physiological (e.g. 25-40°C)
temperatures, more particularly £or non-zero nuclear
spin imaging nuclei in a ^hydrogenated substrate a
distribution in which th§ population difference between
ii ground and excited nuclear spin states is greater than
the equilibrium population difference.
By "imaging nuclei" j;is meant the nuclei in the
hydrogenated substrate responsible for the MR signal
used in MRI to generate images. Thus, for example, the
imaging nucleus might be la 13C or l5N nucleus, generally
up to 4 bonds away from a. XH or 2H nucleus introduced by
hydrogenation of the substrate, or it may be a *H or a 2H
nucleus introduced by hydrogenation of a non-symmetric
unsaturated substrate. [(Since the substrate is
unsymmetrieal the resonance frequencies of the two
introduced hydrogens will not be the same).
While W099/24080 does describe means by which para-
hydrogen hydrogenation may be effected, we have now
found that hydrogenation to harness for MRI the p-H, and/
or o-Dj induced hyperpolarization, the hydrogenation
reaction is particularly j favourably performed by mixing
gaseous para-hydrogen and/or ortho-deuterium enriched
hydrogen (i.e. where the p:o ratio of lH2 is greater than
1:3, particularly greater than '3:7, more particularly
greater than 1:1 and/or the o.-p ratio of 2H8 is greater
than 3:2, particularly greater than 3:1, more
particularly greater than 4:1) with a spray of a
solution of the unsaturated compound and a hydrogenation
catalyst
Viewed from one aspect the invention thus provides
a process for the preparation of an WR contrast agent,
said process comprising:
4
i) obtaining a solution in a solvent of a
hydrogenatable, unsaturated substrate compound and a
catalyst for the hydrogeration of said substrate
compound;
ii) introducing said solution in droplet form into a chamber containing hydrogen gas (H.) enriched in para-hydrogen (p-'H;) and/or ortho-deuterium (o--H-J whereby to hydrogenate said subatrarte to. form a hydrogenated
imaging agent;
iii) optionally subjecting said hydrogenated
imaging agent to a magnetic field having a field
strength below earth's ambient field strength?
iv) optionally dissolving said imaging agent in an aqueous medium; -:
v) optionally separating said catalyst from the solution of said imaging agent in-said aqueous medium;
vi) optionally separating said solvent from the
solution of said imaging agent in said aqueous medium;
and
vii) optionally freezing the solution of said imaging agent in said aqueous medium.
In optional step (iii) of the process of the . invention, the hydrogenated imaging agent is subjected . to a low magnetic field treatment - this step is desirably effected unless the MR imaging procedure is to use as imaging nuclei deuterans introduced by deuteration with ortho-Dl (i.e. gas comprising D2 where the o-D2:-D3 ratio is greater than 2:1). The low field treatment may be effectea at any stage following onset of hydrogenation, and inpeed the process of the invention may be performed in its entirety in a low field; however it is desirable that the low field treatment occur before water addition (optional step (iv)) in order both...to avoid enhancement by the low field of hyperpolarization loss induced by paramagnetic materials which may be present (e.g. as minor impurities, or as dissolved oxygen) in the water and
-5-


because protons in the wafer would themselves have a
relaxing effect. Accordingly it is preferred that the
low field treatment be of-:the hydrogenation reaction
medium (e.g. by placing » least part of the chamber in
a low field) and/or of th| reaction medium drawn out
from the chamber. Low field treatment {e.g. at fields
below 50 n-Tr preferably less than 1 mT, most preferably
less than 0.1T) may be achieved by magnetic shielding
using commercially available materials, e.g. /i-metal,
and may be particularly suitably achieved by disposing
some or all of. the apparatus used for the process of the
invention in a magnetically shielded container such as
is described in WO99/17304.
The low magnetic field treatment may alternatively be effected by passage through a twin. m-metal layer tube, capable of giving '-as field of less' than l mT, more preferably less than 0.5 mT, most preferably less than 0.1 mT, inside.
Preferably, the low field treatment may be effected by passage through a magnetically shielded area with a special magnetic field profile. The magnetic screen is a multi-layer tube of m-metal with the layers arranged so that the sample leaves the earth's magnetic field and enters an area with a field lower than 0.1 mT in just a few me. The sample is then gradually returned to the earth's magnetic field by a combination of a spiral-shaped tube and a lower degree of magnetic shielding. This effects an efficient transfer of polarisation from protons to the hetero-nucleus.
This cycling of the external magnetic field from "earth-field" to less than 1 mT, preferably about 0.1 , . mT, and then gradually back again enables polarisation to be tranaferred from protons in the freshly
-hydrogenated -contrast-...agant. to. a nucleus within the same molecule with a longer polarisation life-time, preferably a *3C or 13 N atom. The timing of this process is critical. For the process to work as effectively as
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possible the sample should leave the earth-field

suddenly and then gradually return to earth field. In the present context, "suddenly" means of the order of s 1 ms and "gradually" means of the order of 10-10000 ms, preferably 100-1000 mL
The magnetic-field screen can be made from /i-metal and can consist of three concentric tubes, for example with diameters of 80, 25 and 12 mm, respectively. At one end of the screen all three layers overlap to give maximal screening and the glass tube is straight and with an inner diameter of, for example l mm. Prom the middle of the screen only the outer layer of screening is kept and the tube apirals out and the inner diameter is increased to, for example 3 mm, to give a more gradual increase in the rield; The spiral continues past the screen for a -few centimeters,
The magnetic screen is also equipped with demagnetization coils sir be the m-metal is slowly magnetized by external fields, especially in the vicinity of imaging magnets. The demagnetization process involves running AC current of approximately, 5A and 5Q Hz through the demagnetization coils and then gradually decreasing the current to zero. The whole process should take between one and a few minutes and preferably be performed an a daily basis. The coils can be made from' 1 mm varnished copper wire and can have in total approximately 2000 turns.
A stopped flow system is where the newly-produced para-hydrogenated product is passed into a resistive magnet (coil) inside a magnetically shielded region. The magnetic screen may be a two-layer tube of /x-raetal with such screening capacity that the residual field is less than 0.1 /*T when no current is flowing in the coil, initially, "when 'the sample enters the coil,- the -current-is on to produce a magnetic field of the order of the earth's field. The current is then turned off and then gradually increased back I to the original. This effects
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an efficient transfer_ of bolarization., from, protons.-to -
the hetero-nucleue, |
Most imaging agents kill require this low magnetic
field treatment for one off two reasons, first that this
promotes polarization transfer from the introduced 'H or
-'H nuclei to the imaging muclei (e.g. l,C, ' 'N, etc.) and
secondly as the treatment: transforms the line shape of
the MR signal from an antli-phase multiplet with zero
integral to a multiplet with a net signal which is good
for imaging. |
The hydrogenatable substrate used may be a material
such as is discussed in W099/24080 as a para-
hydrogenation substrate. I For in vivo imaging studies, the substrate is preferably a material which is physiologically tolerable! both in hydrogenated and unhydrogenated forms. For 5D-MR studies, the substrate is desirably non-symmetrical about the unsaturated bond which is hydrogenated, especially preferably nonsymmetrical within 4 bonds of the unsaturated bond (e.g. H5C2OOCCH;CH«CH-CH3 would be considered to be unsymmetrical within 2 bonds of the ethylenic C:C double bond).
For in vitro or vivo MR studies of biological or
i
quasi-biological processes or synthetic polymer (e.g.
1
peptide, poly-nucleic acid etc.) syntheses, the substrate is preferably hydrogenatable to form a molecule participating in such reactions, e.g. an amino acid, a nucleic acid, a Receptor-binding molecule, etc., either a natural such molecule or an analog.
The solvent used in step (i) of the process of the invention may be any convenient material which serves as a solvent for the substrate and the hydrogenation catalyst. Preferably however it is a volatile organic solvent (e.g. acetone) especially one which is water
miscible, especially preferably it is not water (i.e.
not 1H2O) and especially preferably it is perdeuterated
(e.g. c2H3OC2H3 or dt-acetone) . Where the imaging agent


is for use in in vivo MR investigations, the solvent is preferably physiologically tolerable. Solvent removal (optional process step (vi)) is preferably effected by vacuum, e.g. by spray-flash distillation. Other rapid solvent removal techniques, e.g. affinity techniques, may however be used. .'
The solvent is preferably used at or near the
i:
minimum quantities required to maintain substrate, catalyst and imaging agent in solution during the hydrogenation reaction- |
Alternatively, the reaction may be performed directly in water using ai water-soluble substrate and a water-soluble catalyst. !The process in this case is
both simpler and faster 4s the step of solvent removal

is not then required.
'
The hydrogenation catalyst is preferably a catalyst
as discussed in WO99/24080, e.g. a metal complex, in
particular a rhodium complex..
The enriched hydrogen, which may be pure 1H2 or a mixture of 2H2 and '%__ (perhaps containing some HD) , optionally "containing other gases although preferably free from oxygen or other reactive or paramagnetic gases, may be prepared hi cooling hydrogen (i.e. lH2, 2H2: etc.), preferably to a temperature below 80K, more preferably to a temperature below 30K, still more preferably to a temperature below 22K, and allowing the nuclear spin states to equilibrate, optionally in the presence of a solid phase equilibration promoter, e.g. Fe30 For the hydrogenation reaction, enriched hydrogen is filled into a reaction chamber optionally under


-9-
pressure, e.g. SO to lO0 bar, and the catalyst and substrate solution is introduced in droplet form, e.g. by spraying or atomizing into this reactor. If desired, the solution may be produced by mixing separate solutions of catalyst and of substrate. To ensure proper mixing, a distributor or a plurality of spray nozzles may be used and the chamber contents may be mixed, e.g. by a mechanieal stirrer or by appropriately shaping the chamber walls where there is a flow of reaction mixture in the chamber. The spray-nozzles are advantageously, of the pneumatic-type where para-hydrogen is used as the atomising]!gas. Such nozzles give a better mixing of gas and illiquid, smaller droplets and faster spraying than hydrostatic spray nozzles. The process may be performed continuously with a flow reactor, e.g. a loop or tube reactor, or alternatively
it may be a batch-wise process. Preferably however
there will be a continuous or puleed flow of enriched
hydrogen and solution-spray into the reactor, a
continuous or batch-wise\removal of liquid solution from
the base of the reactor Sand a continuous or batch-wise
venting of unreacted gas from the reactor. The enriched
hydrogen and solution passing into the reactor are
preferably temperature-controlled to ensure the gas-
droplet phase in the realtor ip at the desired
temperature. This can b4 achieved by providing input
lines with temperature sensors and heating or cooling
jackets.
Following hydrogenation and any optional, although generally preferred low magnetic field treatment, the imaging agent is preferably mixed -with water. The water used is preferably sterile and also preferably essentially free of paramagnetic contaminants. The resultant aqueous, solution is then preferably treated to remove the hydrogenation catalyst, e.g, by passage through an ion exchange column, preferably one free of paramagnetic contaminanta. The water may be
10

temperature-controlled as may be a mixing chamber where
water and imaging agent solutions are mixed so as to
ensure the aqueous solution enters the ion exchange
column at the appropriate; temperature. Strongly acidic,
sodium ion charged ion exchange resins such as DOWSX
1x2-400 (Dow Chemicals) and Amberlite IR-120 (both
available from Aldrich Chemicals) resins may
conveniently be used for the removal of typical metal
complex hydrogenation catalysts. For fast ion exchange,
the resin is preferably cross-linked to only a low
degree, e,g. a. '2% divinyl; benzene cross-linked
sulphonated, sodium ion lbaded polystyrene regin.
Removal of the non-agueous' splvent may then
conveniently be effected by spray flash distillation -
e.g. by spraying the aqueous solution into a chamber,
applying a vacuum, and driving' the organic solvent free
aqueous solution from the; chamber using an inert,
preferably non-paramagnetic gas, e*g. nitrogen. Indeed
in general the flow of liguid components through the
hydrogenation apparatus will preferably be effected using applied nitrogen preseure, e.g. 2 to 10 bar.
The resulting aqueous imaging agent solution may be
frozen and stored or alternatively may be used directly
in an MR imaging or spectroscopy procedure, optionally
after dilution or addition of further solution
components, e.g. pH modifiers, complexing agents, etc.
Such direct use may for example involve continuous
infusion or alternatively! injection or infusion of one
or more dose units. Bolus injection is particularly
interesting.
The whole process from beginning of hydrogenation to end of solvent removal may conveniently be effected in less than 100 seconds ,f indeed it is feasible to produce "dosage unite in as little--as 10 to-20-.seconds, which is substantially less than T, for the imaging nuclei in many of the imaging agents in the contrast media so produced.

Desirably, the surfaces contacted by the imaging
agent during the process of the invention are
substantially free of paramagnetic materials, e.g. made
of glasses as used for hyperpolarized He containment as
discussed in WO99/17304 or gold or a deuterated polymer.
Surfaces contacting the non-aqueous solvent (e.g.
acetone) should be acetone-resistant and valves may be
magnetically controlled with solvent resistant Teflon or
silicon parts.
The process of the invention may conveniently be
automated and computer-controlled.
Viewed from a further aspect the invention provides a hydrogenation apparatus comprising a hydrogenation chamber having a liquid' outlet into a conduit leading to a liquid droplet generator inlet (e.g. a spray nozzle) to a solvent removal chamber,
said hydrogenation chamber having a hydrogen inlet and a solution inlet provided with a further liquid droplet generator,
said conduit including a catalyst removal chamber (e.g. containing ah ion Exchange resin) between said hydrogenation chamber an(| said solvent removal chamber and being provided, preferably between said hydrogenation chamber and said catalyst removal chamber, with a liquid inlet (e.g a water inlet), said solvent removal chamber being provided with a gas outlet (e.g. attached to a vacuum source) and with a liquid outlet (e.g. to an optional formulation chamber and thence to administration means or |o a dose unit receiver (e.g. a syringe)), and
said hydrogenation Apparatus being further provided with magnetic shielding such that the magnetic field within at least part of said hydrogenation chamber and/ or within at least part pf said conduit (preferably the part upstream of the liquid (water) inlet) is Clearly, if the process of the invention is
12
performed directly in water using a water-soluble
substrate and water-soluble catalyst, then the solvent
removal chamber is not required.
The apparatus of the] invention is preferably also
provided with reservoirs and mixing chambers appropriate
for the materials being fed in, e.g. an enriched
hydrogen reservoir, a water reservoir, a reservoir for
solutions of hydrogenation catalyst and/or
hydrogenatable substrate, I reservoirs for further
contrast medium components, a mixing chamber for mixing
solutions of catalyst and substrate, a mixing chamber
fox mixing water with the; solution exiting the
i
hydrogenation chamber, etc. likewise the hydrogenation chamber is preferably provided with a vent for removing
hydrogen and various of the chambers and reservoirs are
preferably provided with hitrogen sources and nitrogen
inlets to drive their consents into or through the
i
apparatus. Particularly preferably, the apparatus also includes an enriched hydrogen generator, valves, valve actuators and a computer control for controlling apparatus operation.
The magnetic shielding is preferably removable so that it can be removed is 2H-imaging is desired.
The chambers and cordluits of the apparatus of the
invention are preferably sealable to prevent ingress of
air; moreover, the apparatus is preferably provided with
valves and ports arrangesble to permit degassing, in
particular to remove surface adsorbed oxygen.
The water input to the apparatus of the invention
is preferably deoxygenated, e.g. by treatment with
nitrogen-
The "chambers" in the apparatus of the invention
may have internal cross-sectional areas which are larger
than the internal cross-sectional areas of the chamber
inlets or outlets (in the! flow direction) ; alternatively
the cross-sectional areas in the flow direction may be substantially invariant, i.e. a tube may function as

inlet-chamber-outlet -
The use of homogeneously catalysed »spray-hydrogenation" in the preparation of MR contrast agents la new. Likewise such hydrogenation is new in the preparation of amino acids and pharmaceuticals. The procedure is rapid and efficient and this forma a further aspect of the invention. Viewed from this aspect the invention provides a process for the preparation of an amino acid, a pharmaceutical or an in vivo diagnostic agent, characterised in that said process comprises a hydrodenation atep in which a solution of a substrate arid a hydrogenation catalyst is sprayed into a, hydrogen-containing chamber.
Where the hydrogenation is effected using a gas in ' which the !H:;H ratio is i| excess of 9:1, using p-D2, the use of heterogenous catalysis is also contemplated -in this event catalyst removal may involve filtering or other particulate removal [techniques.
The contents of all tublications referred to herein are hereby incorporated by reference.
Embodiments of the process and apparatus of the invention will now be described with reference to the following non-limiting Example and to the accompanying drawings, in which:
Figure l is a schematic view of ,one apparatus according to the invention,-
Figure 2 is a schematic view of part of the apparatus of Figure l; |
Figure 3 is a schematic view of a further part of the apparatus of Figure i| and
Figure 4 is a aehematic view of a further aspect of the present invention.
Referring to Figure 1, hydrogen (1H2) from cylinder 1 is fed via tube 2 to a p-1H2 generator and thence into hydrogenation chamber 3. j& hydrogenation catalyst solution from reservoir 4 land a hydrogenatable substrate solution from reservoir 5 are fed via lines 6 and 7 to a
14
spray nozzle in chamber 3|. The liquid settling in chamber 3 passes via conduit 8 through a twin m-metal layered tube 9, a magnetic: shield having an internal field of less than 0.1 mT, into an ion exchange column 10 and thence to a spray nozzle in the solvent removal chamber 11. Before the liquid enters the ion exchange column but after it exits); the magnetic shielding, water from reservoir 12 is added via tube 13. Solvent removal chamber 11 is connected via tube 14 to a vacuum pump 15 which serves to remove non-aqueous solvent, e.g. acetone. The liquid remaining in chamber 11 is removed via exit duct 16.
Referring to Figure k, it can be seen, that nitrogen (at 3 bar) is used to drive catalyst and substrate solutions from reservoirs I 4 and 5 to a water-jacketed mixing chamber 17 and the lice to the spray nozzle 18 {which may be pneumatic) in hydrogenation chamber 3 which is provided with a valved hydrogen vent IS. Alternatively, the dosage and mixing of substrate and catalyst may be controlled by computer controlled pumps (not shown). Nitrogen may be used to drive the liquid
collecting in. the hydrogenationa chamber through the
j1
magnetic shielding 9 to mix with nitrogen driven water , from reservoir 12. Turning to Figure 3, the solution/water mixture pa bees into water-jacketed mixing chamber 20 and thence thrbugh a 2 to 4 cm long ion exchange column 10 containing 400 mesh eulphonated polystyrene/2% DVB and on to spray nozzle 21 in solvent removal chamber 11. To eisure complete non-aqueous polvent removal, the chamber 11 is buffered with a cooling trap (not shown) followed by a second volume before the vacuum pump - phis relieves the very sudden load otherwise put on the j pump. After release from the -chamber n, -the aqueous "Contrast medium" is_ready far use; alternatively its pH may be buffered and its ion profile adjusted (e.g. to add plasma cations).
i
There are two preferred modes of operation; in one
15

the apparatus is used to fill a syringe which is removed
and the contrast medium is injected; in the second, the
apparatus delivers email doses of contrast medium
continuously to a catheter linked to the patient. The
second mode allows tor easier imaging since the operator
can adjust the MR imager to obtain a satisfactory image.
Referring to Figure J4, the hyperpolarised solution
is delivered by the apparatus 30 into a syringe 31. A
3-way switching valve 32 is connected. The syringe
should be positioned vertically with the plunger-handle
up to e-nsure the solution; is free of air. By switching
the valve 32 the solution can be injected to the
transfer tube 33. A syringe or cavity 34 with
determined volume and low friction is connected just
before the injection tare let 35, and the syringe 34
absorbs the dead space ar& possible gas bubbles.
EXAMPLE 1
A solution of {bicyclo(2-2.l)hepta-2,5-diene}-Cl.4-bia (diphenylphosphino) butane] -rhodium(I) tetrafluoroborate (93.5mg) in argon-bubbled acetone (5ml) is charged in chamber A and a solution of 2-acetoxyacrylic acid (UQtijg, 0.85mmola) in argon-bubbled acetone (5ml) in chamber JB. Chamber E is filled with distilled, argon-bubbled (water. Ion exchange resin of type sulphonated polystyrene, 2% cross-linked, swelled with water and charged with sodium ions is loaded in the ion-exchange column. water at 42°c is circulated through the jackets in the Bet-up. The experiment is started by running a computer program that controls the valves according to schemie l as shown in Table l below. The program is written or LabView. After the program is finished the ""sample of '"aqueous hyperpolarized" aoetyl lactic acid is removed at the bottom of chamber G by a syringe.
A 3m3/hr 2-stage diabhragm pump ia used to provide

16
the vacuum and 3 bar of nitrogen is used as the driving
pressure.
The spray nozzles are ordinary commercial oil-burner nozzles, the one in. chamber D is specified as 1.5 U$ gallon/hr with a 60° cone angle, the one in chamber G is 1.0 US gallon/hr with a 80s cone angle.
The magnetic valves fare BW, 24V DC with gaskets of
EPDM.
The magnetic screen Is made from two concentric
tubes of m-metal. '
- 17-




The hyperpolarized Solution is delivered by the para-hydrogen contrast agent apparatus to which a tube of length e.g. 50 mm is connected. A 3-way switching valve is connected to this tube, as a syringe. The syringe is placed vertically with the plunger pointing up to ensure the solution is free from air. The bubbles will float to the top and stay there. By switching the valve the solution can be injected into the transfer tube e.g. of length 3200mm and a diameter of 0.76 mm. This gives a dead-volume of 1,5 ml. Just before the cannula "injection targei" (e.g. .a venflon or butterfly) a syringe with determined volume and low friction is connected with a 3-way be. This syringe will collect the dead space and possible gas bubbles from transfer tubes. The plunger of the syringe is prevented from leaving the barrel by a top-screw. When the syringe is full, the injected solution proceeds by the cannula to the target. Syringes with ground-glass barrel and plunger are suitable for!; this set-up.
With the equipment »described above it was possible to inject 0.33 ml/s of physiological saline into the tail-vein of a rat.
19
WE CLAIM:
1. A process for the preparation of an MR contrast agent, said process
comprising:
i) obtaining a solution in a solvent of a hydrogenatable, unsaturated substrate compound and a catalyst for the hydrogenation of said substrate compound:
ii) introducing said solution in droplet form into a chamber containing hydrogen gas (H2) enriched in para-hydrogen (p-1H2) and/or ortho-deuterium (o-2H2) whereby to hydrogenate said substrate to form a hydrogenated imaging agent;
iii) optionally subjecting said hydrogenated imaging agent to a magnetic field having a field strength below earth's ambient field strength; iv) optionally dissolving said imaging agent in an aqueous
medium;
v) optionally separating said catalyst from the solution of said
imaging agent in said aqueous medium;
vi) optionally separating said solvent from the solution of said
imaging agent in said aqueous medium; and
vii) optionally freezing the solution of said imaging agent in said aqueous medium.
2. A process as claimed in claim 1, wherein said field strength in step (iii) is less than 50 mT.
3. A process as claimed in claim 1, wherein said field strength in step (iii) is less than 1 mT.
4. A process as claimed in claim 1, wherein said field strength in step (iii) is less than or equal to 0.1 mT.
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5. A process as claimed in claim 1, wherein said field strength in step (iii) is cycled from earth's ambient field strength to a field strength less than 0.1 mT, then back to ambient field strength again.
6. A process as claimed in claim 5, wherein the first part of the cycle is of the order of £ 1 ms and the second part is of the order of 10-10000 ms.
7. A process as claimed in any one of the preceding claims wherein said process is carried out directly in water and wherein both said substrate and said catalyst are water-soluble.
8. A process for the preparation of an amino acid, a pharmaceutical or an in vivo diagnostic agent, wherein process comprises a hydrogenation step in which a solution of a substrate and a hydrogenation catalyst is sprayed into a hydrogenation containing chamber.



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Documents:

abstract1.jpg

in-pct-2001-01327-mum-cancelled pages(1-1-2008).pdf

in-pct-2001-01327-mum-claims(24-10-2001).pdf

in-pct-2001-01327-mum-claims(complete)-(24-10-2001).pdf

in-pct-2001-01327-mum-claims(granted)-(14-9-2010).pdf

in-pct-2001-01327-mum-claims.doc

in-pct-2001-01327-mum-claims.pdf

in-pct-2001-01327-mum-correspondence(1-1-2008).pdf

in-pct-2001-01327-mum-correspondence(17-8-2005).pdf

IN-PCT-2001-01327-MUM-CORRESPONDENCE(20-4-2009).pdf

in-pct-2001-01327-mum-correspondence(ipo)-(15-9-2010).pdf

in-pct-2001-01327-mum-correspondence(ipo)-(19-9-2008).pdf

in-pct-2001-01327-mum-correspondence-others.pdf

in-pct-2001-01327-mum-correspondence-received-ver-031201.pdf

in-pct-2001-01327-mum-correspondence-received-ver-041201.pdf

in-pct-2001-01327-mum-correspondence-received-ver-080802.pdf

in-pct-2001-01327-mum-correspondence-received-ver-141201.pdf

in-pct-2001-01327-mum-correspondence-received-ver-240404.pdf

in-pct-2001-01327-mum-correspondence-received-ver-241001.pdf

in-pct-2001-01327-mum-correspondence-received.pdf

in-pct-2001-01327-mum-descripiton (complete).pdf

in-pct-2001-01327-mum-description(complete)-(24-10-2001).pdf

in-pct-2001-01327-mum-description(granted)-(14-9-2010).pdf

in-pct-2001-01327-mum-drawing(24-10-2001).pdf

in-pct-2001-01327-mum-drawing(amended)-(17-8-2005).pdf

IN-PCT-2001-01327-MUM-DRAWING(AMENDED)-(26-7-2005).pdf

in-pct-2001-01327-mum-drawing(granted)-(14-9-2010).pdf

in-pct-2001-01327-mum-drawings.pdf

in-pct-2001-01327-mum-form 1(1-1-2008).pdf

in-pct-2001-01327-mum-form 1(26-7-2005).pdf

IN-PCT-2001-01327-MUM-FORM 1(8-8-2002).pdf

in-pct-2001-01327-mum-form 13(1-1-2008).pdf

in-pct-2001-01327-mum-form 13(8-8-2002).pdf

in-pct-2001-01327-mum-form 19(20-4-2004).pdf

in-pct-2001-01327-mum-form 2(24-10-2001).pdf

in-pct-2001-01327-mum-form 2(complete)-(24-10-2001).pdf

in-pct-2001-01327-mum-form 2(granted)-(14-9-2010).pdf

in-pct-2001-01327-mum-form 2(title page)-(24-10-2001).pdf

in-pct-2001-01327-mum-form 2(title page)-(amended)-(8-8-2002).pdf

in-pct-2001-01327-mum-form 2(title page)-(complete)-(24-10-2001).pdf

in-pct-2001-01327-mum-form 2(title page)-(granted)-(14-9-2010).pdf

in-pct-2001-01327-mum-form 3(24-10-2001).pdf

in-pct-2001-01327-mum-form 3(26-7-2005).pdf

in-pct-2001-01327-mum-form 5(24-10-2001).pdf

in-pct-2001-01327-mum-form 5(8-8-2002).pdf

in-pct-2001-01327-mum-form-1.pdf

in-pct-2001-01327-mum-form-13.pdf

in-pct-2001-01327-mum-form-19.pdf

in-pct-2001-01327-mum-form-2-1.doc

in-pct-2001-01327-mum-form-2.doc

in-pct-2001-01327-mum-form-2.pdf

in-pct-2001-01327-mum-form-26.pdf

in-pct-2001-01327-mum-form-3-ver-250705.pdf

in-pct-2001-01327-mum-form-3.pdf

in-pct-2001-01327-mum-form-pct-ipea-409.pdf

in-pct-2001-01327-mum-form-pct-ipea-416.pdf

in-pct-2001-01327-mum-form-pct-isa-220.pdf

in-pct-2001-01327-mum-form-pct-separate sheet-409.pdf

in-pct-2001-01327-mum-pct-search report.pdf

in-pct-2001-01327-mum-petition under rule 137(26-7-2005).pdf

in-pct-2001-01327-mum-petition under rule 138(26-7-2005).pdf

in-pct-2001-01327-mum-power of attorney(18-12-2001).pdf

in-pct-2001-01327-mum-power of authority(26-7-2005).pdf

in-pct-2001-01327-mum-specification(amanded)-(1-1-2008).pdf

in-pct-2001-01327-mum-specification(amended)-(17-8-2005).pdf

IN-PCT-2001-01327-MUM-SPECIFICATION(AMENDED)-(26-7-2005).pdf

in-pct-2001-01327-mum-wo international publication report(24-10-2001).pdf

IN-PCT-2001-1327-MUM-CORRESPONDENCE(20-4-2009).pdf

in-pct-2001-1327-mum-form 13(12-5-2009).pdf


Patent Number 242822
Indian Patent Application Number IN/PCT/2001/01327/MUM
PG Journal Number 38/2010
Publication Date 17-Sep-2010
Grant Date 14-Sep-2010
Date of Filing 24-Oct-2001
Name of Patentee GE HEALTHCARE AS
Applicant Address Norwegian Company, Nycoveien 2, 0485 Oslo,
Inventors:
# Inventor's Name Inventor's Address
1 OSKAR AXELSSON Nycomed Innovation AB, Medeon Malmo, Per Albin Hanssons Vag 41, S-205 12 Malmo
2 AXEL MORGENSTJERNE Dangaardsvej 6, 11th DK-2800 Lyngby, Denmark
3 CHARLOTTE OLOFSSON Nycomed Innovation AB, Medeon Malmo, Per Albin Hanssons Vag 41, S-205 12 Malmo
4 GEORG HANSSON c/o Nycomed Innovation AB Medeon Malmo, Per Albin Hanssons Vag 41, S-205 12 Malmo
5 HAUKAR JOHANNESSON Nycomed Innovation AB, Medeon Malmo, Per Albin Hanssons Vag 41, S-205 12 Malmo
6 JAN HEARIK ARDENKJAER LARSEN Nycomed Innovation AB, Medeon Malmo, Per Albin Hanssons Vag 41, S-205 12 Malmo
PCT International Classification Number A61K49/00
PCT International Application Number PCT/GB00/01897
PCT International Filing date 2000-05-17
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 9911681.6 1999-05-19 U.K.