Imaging agents, precursors thereof and methods of manufacture

Details Imaging agents, precursors thereof and methods of manufacture Imaging agents, precursors thereof and methods of manufacture

2001-06-04

2004-11-30

Hartley, Michael G. (Department: 1616)

Drug, bio-affecting and body treating compositions

Radionuclide or intended radionuclide containing; adjuvant...

In an organic compound

C424S001890

Reexamination Certificate

active

06824760

ABSTRACT:

BACKGROUND OF THE INVENTION
Short half-lived radioactive compounds are useful as imaging agents to diagnose cancers and abscesses. In the routine production of such imaging agents, safety and production considerations must be taken into account. It is advantageous to minimize contact time while ensuring quick and consistent production of the imaging agents.
There are generally two types of imaging procedures conducted. In positron emission tomography (PET), two beta rays emitted from the decaying radionuclide are detected. In single photon emission computed tomography (SPECT), one beta ray emitted from the decaying radionuclide is detected. PET provides a more exact location of tumors. However, SPECT is simpler and easier to use, and is therefore used more often.
Generally speaking, PET uses radio-compounds labeled with the positron-emitters such as
18
F,
11
C,
13
N and
15
O, SPECT uses radio compounds labeled with the single-photon-emitters such as
18
F,
11
C,
13
N and
15
O, although
75
Br and
124
I can also be used. SPECT, on the other hand, generally uses radionuclides that have more neutrons than protons, such as
67
Ga,
77
Br,
123
I,
124
I,
125
I,
126
I,
131
I and
201
TI.
In the art, glucose-based and amino acid-based compounds have been used as imaging agents. Amino acid-based compounds are more useful in analyzing tumor cells, due to their faster uptake and incorporation into protein synthesis. Of the amino acid-based compounds,
11
C- and
18
F-containing compounds have been used with success.
11
C-containing radiolabeled amino acids suitable for imaging include, for example, L-[1-
11
C]leucine (Keen et al.
J. Cereb. Blood Flow Metab
. 1989 (9):429-45), L-[1-
11
C]tyrosine (Wiesel et al.
J. Nucl. Med
. 1991 (32):2041-49), L-[methyl-
11
C]methionine (Comar et al.
Eur. J. Nucl. Med
. 1976 (1):11-14) and L-[1-
11
C]methionine (Bolster et al.
Appl. Radiat. Isot
. 1986 (37):1069-70). However,
11
C-containing radiolabeled amino acids have limited applicability, due to the short half-life of
11
C (T
1/2
=20 min.). Therefore, great effort was directed toward the synthesis and evaluation of other radionuclides, such as those listed above. Two
18
F-containing radiolabeled amino acids, 4-[
18
F]fluoro-L-phenylalanine and 2-[
18
F]fluoro-L-tyrosine, exhibit protein incorporation, but can only be synthesized with uncorrected yields less than 5%. See Arnstein et al.
Biochem. J
. 1984 (1):340-46 and Coenen et al.
Radioisot. Klinik. Forschung
1988 (18):402-40.
More recently, position 2- and 3-L-[
18
F]fluoro-&agr;-methyl tyrosine have been synthesized by electrophilic substitution (Tomiyoshi et al.
Nucl. Med. Commun
. 1997 (18):169-75). Unfortunately, the radiochemical yield from such a production is low. Another more recent compound to be synthesized is o-(2-[
18
F]fluoroethyl)-L-tyrosine (Wester et al.
J. Nucl. Med
. 1999 (40):205-212). This paper describes the synthesis of the target compound, using a nucleophilic reaction, in a 40-60% yield. However, the reaction requires a two-step synthesis.
SUMMARY OF THE INVENTION
An object of the present invention is to develop new imaging agents suitable for use in PET and SPECT and which overcome the disadvantages of known compounds.
Another object of the present invention is to provide a method of manufacturing such compounds via the nucleophilic route using a one-step synthesis.
A further object of the invention is to provide precursors useful for manufacturing the new imaging agents of the invention.
These objects are achieved by the present invention.
The present invention includes compounds of formula (I), or pharmaceutically acceptable salts thereof:
wherein
the C marked with an asterisk represents a chiral center and the compound is present in the L-form, the D-form or as a racemic mixture;
R
1
is selected from the group consisting of a single bond, phenyl, and a group of formula (a), (b), (c) or (d)
The present invention also includes compounds of formula (II), which are useful for preparing the compounds of formula (I):
wherein
R
1
is the same as indicated for the compounds of formula (I);
R
2
is H or a group —R
3
—O—R
4
, wherein R
3
is C
1
-C
7
alkyl and R
4
is H or a leaving group, preferably a sulfonyl group such as tosyl, trifyl, mesyl, trimsyl, tripsyl, brosyl or nosyl;
PG
1
is a carboxyl protecting group; and
PG
2
is an amino protecting group.
The present invention also includes a method of synthesizing compounds of formula (I) by reacting a compound of formula (IIc):
wherein R
1
, R
2
, PG
1
and PG
2
are the same as indicated for the compounds of formula (I), and R
3
is a leaving group, preferably a sulfonyl group such as tosyl, trifyl, mesyl, trimsyl, tripsyl, brosyl or nosyl,
with a salt of RE, where RE is the same as indicated for the compounds of formula I, to produce a compound of formula (Ia):
wherein R
1
, R
2
, RE, PG
1
and PG
2
are the same as above; and removing the protecting groups.
In this invention, compounds of formula I have been developed:
wherein
the C marked with an asterisk represents a chiral center and the compound is present in the L-form, the D-form or as a racemic mixture; R
1
is selected from the group consisting of a single bond, phenyl, and a group of formula (a), (b), (c) or (d)
R
2
is C
1
-C
7
alkyl; and
RE is selected from the group consisting of
11
C,
13
N,
15
O,
18
F,
67
Ga,
75
Br,
77
Br,
123
I,
124
I,
125
I,
126
I,
131
I, and
201
TI, preferably
123
I,
125
I, and
18
F.
Preferably, R
1
is phenyl. When R
1
is phenyl, the —O—R
2
—RE group can be para, meta or ortho the CH
2
group. It is preferred that the —O—R
2
—RE group is para the CH
2
group.
R
2
is preferably C
2
-C
6
alkyl, more preferably C
2
-C
5
alkyl. It is most preferable that R
2
is propyl.
The compounds of formula (I) contain a chiral center at the &agr;-C. The compounds of the invention can therefore be present in the L-form, the D-form, or as a racemic mixture. It is preferred that the compounds be present in the L-form.
The present invention also includes compounds of formula (II):
wherein
R
1
is the same as indicated for the compounds of formula (I);
R
2
is H or a group —R
3
—O—R
4
, wherein R
3
is C
1
-C
7
alkyl and R
4
is H or a leaving group, preferably a sulfonyl group such as tosyl, trifyl, mesyl, trimsyl, tripsyl, brosyl or nosyl;
PG
1
is a carboxyl protecting group; and
PG
2
is an amino protecting group.
The compounds of formula (II) are useful as intermediates in the preparation of compounds of formula (I).
More specifically, the compounds of formula (II) may be divided into subgroups (IIa), (IIb) and (IIc):
which are important intermediates in the preparation of compounds of formula (I),
wherein in each case
R
1
and R
2
are the same as indicated for the compounds of formula (I);
R
3
is a leaving group, preferably a sulfonyl group such as tosyl, trifyl, mesyl, trimsyl, tripsyl, brosyl or nosyl;
PG
1
is a carboxyl protecting group; and
PG
2
is an amino protecting group.
As noted above, the leaving groups for compounds of formula (II) are preferably sulfonyl groups, however any suitable leaving group can be used, as known to those of ordinary skill in the art. Especially preferred are tosyl, trifyl, mesyl, trimsyl, tripsyl, brosyl or nosyl, with tosyl, trifyl and mesyl being more preferred and tosyl being most preferred.
The protecting groups (PG
1
and PG
2
) can be any suitable carboxyl protecting group and amino protecting group, as known to those of ordinary skill in the art. Reference is made to “Protective Groups in Organic Chemistry,” ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, “Protective Groups in Organic Synthesis,” John Wiley & Sons, 1991, each incorporated by reference. PG
1
may be, for example, an alkyl group such as methyl, ethyl or propyl. PG
2
may be, for example, a Boc group.
Generally, the reaction scheme for preparing compounds of formula (I) is as follows. A starting compound of formula (III):

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