Synthesis of 17F labeled fluoroalkanes

Details Synthesis of 17F labeled fluoroalkanes Synthesis of 17F labeled fluoroalkanes

2001-04-30

2003-07-01

Hartley, Michael G. (Department: 1616)

Drug, bio-affecting and body treating compositions

Radionuclide or intended radionuclide containing; adjuvant...

In an organic compound

Reexamination Certificate

active

06585953

ABSTRACT:

FIELD OF THE INVENTION
This invention pertains generally to the production of
17
F and to the synthesis of
17
F labeled fluoromethane and other fluoroalkanes and the use of such labeled materials in positron emission tomography.
BACKGROUND OF THE INVENTION
Positron emission tomography (PET) has found wide application as a diagnostic method. Various radioisotopes have been investigated for application in PET and other diagnostic imaging methods. One of these radioisotopes is
15
O
15
O (t½=122 seconds) tracers such as
15
O labeled water are currently the most commonly used tracers in PET. One advantage of
15
O labeled water as a tracer is that it can be easily and reliably synthesized. A disadvantage, however, is that it has a relatively low permeability surface product such that at high flows, the signal is reduced. Eichling et al.
Circ. Res.
35, 358-364 (1974); Herscovitch et al.
J. Cereb. Blood Flow Metab.
7, 527-542 (1987); Renkin, E. M.
Am J. Physiol.
197, 1205-1210 (1959). Additionally, tracers such as
15
O labeled water are usually administered by injection and are slow to clear test subjects.
Another radioisotope that has been used is
18
F (t½=110 minutes) in tracers such as
18
F labeled fluoromethane which has been used to determine regional cerebral blood flow (rBCF). Gatley, et al.
Int. J. Appl. Radiat. Isot.
32, 211-214, (1981). Because of the relatively long half life of
18
F, tracers labeled with this isotope are ill suited for the fast repetitions necessary for cerebral activation protocols.
The short half life of
17
F (E
&bgr;
+
(max)=1.74 MeV; t½≈64 seconds) suggests that this might be a suitable radioisotope for use in PET. The short half life presents problems, however, in that tracers labeled with this isotope must be prepared quickly in order to preserve the maximum amount of
17
F in a labeled compound.
17
F labeled fluoromethane has been prepared by several routes. For example,
17
F labeled fluoromethane has reportedly been produced by Hunsdiecker like decomposition of
17
F acetyl hypofluorite and by passage of
17
F labeled F
2
through CH
3
HgCl. Mulholland et al.
J. Nuc. Med
28, 1082, (1987). These methods do not produce
17
F labeled fluoromethane in sufficient yield for practical imaging use.
Therefore, a need exits for an improved method of generating
17
F and for producing labeled fluoromethane and other fluoroalkanes from it. A need also remains for improved diagnostic methods using
17
F labeled fluoromethane and other fluoroalkanes.
SUMMARY OF THE INVENTION
The present invention provides
17
F labeled fluoromethane and other
17
F labeled fluoroalkanes, and methods for producing
17
F labeled fluoromethane and other
17
F labeled fluoroalkanes. The invention also provides methods of determining the location of an
17
F labeled tracer.
A method of generating
17
F labeled fluoroalkanes includes contacting
17
F labeled F
2
with an alkane, preferably methane, a substituted or unsubstituted alkene, or a substituted or unsubstituted alkyne in the presence of a metal oxide catalyst to produce the
17
F labeled fluoroalkane. In more preferred embodiments, the
17
F labeled F
2
is contacted with the alkane, the substituted or unsubstituted alkene, or the substituted or unsubstituted alkyne in the presence of the metal oxide catalyst and neon.
In preferred embodiments, the
17
F is generated by proton irradiation of
20
Ne in a target gas stream comprising neon, preferably natural neon gas. In still other embodiments, the target gas stream includes F
2
and neon gas that includes
20
Ne whereas in still other preferred embodiments, the target gas stream includes helium, F
2
, and neon gas that includes
20
Ne.
In preferred embodiments, the
20
Ne is irradiated with protons having an energy of greater than 8 MeV, more preferably with an energy of about 11 MeV. In another preferred embodiment the protons have an energy of about 16 MeV. The protons used to irradiate
20
Ne are preferably generated by a cyclotron.
In another embodiment, the
17
F is generated by deuteron irradiation of
16
O in a target gas stream that includes O
2
.
In preferred processes, the target gas stream preferably comprises less than or about 1.0 percent, more preferably less than about 0.7 percent, and most preferably less than about 0.3 percent of F
2
. In still other preferred embodiments the total pressure of the target gas ranges from about 100 to about 400 psig or more preferably ranges from about 160 to about 240 psig.
In other preferred embodiments of producing
17
F labeled fluoromethane, the
17
F labeled F
2
is contacted with methane, and the metal oxide catalyst is silver oxide, preferably at a temperature ranging from about 200° C. to about 600° C. More preferably, the metal oxide is at a temperature ranging from about 400° C. to about 500° C., and most preferably the metal oxide is at a temperature of about 450° C.
In other more preferred embodiments of producing
17
F labeled fluoroalkanes, the
17
F labeled F
2
is contacted with the substituted or unsubstituted alkene or the substituted or unsubstituted alkyne and the metal oxide catalyst is silver oxide which is more preferably at a temperature ranging from about 10° C. to about 600° C. or still more preferably is at a temperature ranging from about 20° C. to about 100° C. Most preferably, the metal oxide catalyst is at a temperature of about 25° C. in the process for producing
17
F labeled fluoroalkanes.
In still other preferred embodiments, the alkene or alkyne contacted with the
17
F labeled F
2
is a haloalkene or haloalkyne, more preferably a fluorinated alkene or alkyne. Still more preferably, the alkene is a difluoroalkene, yet more preferably 1,1-difluoroethylene such that the
17
F labeled fluoroalkane produced is
17
F labeled 1,1,1,2-tetrafluoroethane where one of the fluorine atoms is an
17
F fluorine atom.
In still other preferred embodiments, the
17
F labeled fluoroalkane is passed through a scrubber, preferably a soda lime scrubber.
In yet other preferred embodiments of the method of generating the
17
F labeled fluoroalkane, the
17
F is continuously generated by continuously irradiating the target gas stream with protons and the
17
F labeled fluoroalkane is continuously produced by continuously contacting the
17
F labeled F
2
with the alkane, the substituted or unsubstituted alkene, or the substituted or unsubstituted alkyne, more preferably methane.
A method of determining the location of an
17
F labeled tracer is also provided. The method includes generating the
17
F labeled fluoroalkane according to the invention; administering the
17
F labeled fluoroalkane to a test subject; and collecting scans of the test subject using a radiosensitive detector. In preferred such methods, the
17
F labeled fluoroalkane is administered to the test subject by having the test subject inhale the
17
F labeled fluoroalkane. In another preferred method of determining the location of an
17
F labeled tracer, the
17
F labeled fluoroalkane is added to a saline solution and the saline solution is administered to the test subject.
Preferred radiosensitive detectors for use in determining the location of an
17
F labeled tracer such as
17
F labeled fluoromethane and other
17
F labeled fluoroalkanes, are selected from a scintillation detector, a Geiger counter, a positron emission tomography scanner, a single photon emission computed tomography scanner, or a solid state detector. More preferred radiosensitive detectors for use in the method of determining the location of an
17
F labeled tracer are positron emission tomography scanners or cameras.
In other more preferred embodiments of producing
17
F labeled fluoroalkanes, the
17
F labeled F
2
is contacted with the substituted or unsubstituted alkene or the substituted or unsubstituted alkyne and the metal oxide catalyst is silver oxide which is more preferably at a temperature ranging from about 10° C. to about 600° C. or still more preferably is at a temperature ranging from ab

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