Organic compounds -- part of the class 532-570 series – Organic compounds – Radioactive metal containing
Reexamination Certificate
2001-12-20
2004-02-24
Jones, Dameron L. (Department: 1616)
Organic compounds -- part of the class 532-570 series
Organic compounds
Radioactive metal containing
C534S007000, C424S001110, C424S001650, C424S009100
Reexamination Certificate
active
06696551
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a chelation complex comprising
225
Actinium (
225
Ac) and 1,4,7,10,13,16-hexaazacyclooctodecane-N,N′,N″,N′″,N″″,N′″″-hexaacetic acid (HEHA) (
225
Ac-HEHA), bifunctional HEHA, bifunctional HEHA-targeting agent, bifunctional
225
Ac-HEHA, bifunctional
225
Ac-HEHA-targeting agent, and methods of synthesis and use, such as in the context of radioimmunotherapy, decontamination and detoxification.
BACKGROUND OF THE INVENTION
In the field of radioimmunotherapy, the radioisotope chosen is determined, at least in part, by the type of disease to be treated. The reason for this is that the type of particles emitted by a given radioisotope are directly related to tissue penetration and the ability of the isotope to kill cells (Boll et al., Radiochim. Acta 79: 87-91 (1997)). &bgr;-emitters, like
90
Y and
131
I, which have a tissue range of several millimeters, have been used successfully to treat solid tumors (Boll et al. (1997), supra). However, a tissue range of several millimeters is not optimal for the treatment of single cells, small clusters of cells, micrometastatic disease, leukemias and lymphomas (Jurcic et al., In:
Cancer Chemotherapy and Biological Response Modifiers Annual
17, Pinedo et al., eds., New York: Elsevier B. V. (1998), pp. 195-216; Falini et al.,
Cancer Surveys
30: 295-309 (1998)). &agr;-emitters, on the other hand, combine high cytotoxicity with a short tissue range, i.e., less than about 150 &mgr; (Boll et al. (1997), supra). Alpha radiation can kill a cell with only one hit to the nucleus and will kill substantially any cell with 10 hits or less. Consequently, considerable effort has been expended in the development of the &agr;-emitters
212
Bi (t
½
=60 min) (Ruegg et al.,
Cancer Res
. 50: 4221-4226 (1990)),
213
Bi (t
½
=45 min) (Geerlings et al.,
Nucl. Med. Comm
. 14: 121-125 (1993)), and
211
At (t
½
—7.2 hr) (Lambrecht et al.,
Radiochim. Acta
36: 443-440 (1985)). However,
212
Bi,
213
Bi and
211
At suffer from disadvantages. The short half-life of
212
Bi and
213
Bi limit their application. The limited available of
211
At, due to half-life and production constraints, limits its utility. Consequently,
225
Ac, which is highly cytotoxic, has been proposed as an alternative &agr;-emitter to
212
Bi,
213
Bi and
211
At for use in radioimmunotherapy.
225
Ac decays through a chain of four &agr; emissions and two &bgr; emissions to the stable isotope
209
Bi, thereby releasing a large amount of energy (28 MeV) (Davis et al.,
Nucl. Med. Biol
., accepted; Alleluia et al., In:
Gmelin Handbook of Inorganic Chemistry
, 8
th
ed., Kugler et al., eds., New York: Springer-Verlag (1981), pp. 181-193). Unfortunately, most of the
221
Ac administered in a dose is deposited in the liver and bone (Beyer et al.,
Isotopenpraxis
26: 111-114 (1990)). Thus, numerous attempts have been made to reduce the toxicity of
225
Ac through chelation with, for example, citrate (Beyer et al. (1990), supra), EDTMP (ethylenediaminetetramethylenephosphonic acid; Beyer et al.,
Nucl. Med. Bio
. 24:367-372 (1997)), EDTA (ethylenediaminetetraacetic acid; Alleluia et al. (1981), supra) and CHXA″-DTPA (N[(R)-2-amino-3-(4-nitrophenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diamine-N,N,N′,N″,N″-pentaacetic acid; Davis et al., supra). While these chelates reduce the liver dose somewhat, CHXA″-DTPA, which is the best
225
Ac chelate to date, still has a maximum tolerated dose (MTD) of approximately 100 kBq in mice and higher doses of
225
Ac-CHX-DTPA have resulted in 100% mouse mortality within eight days (Davis et al., supra).
Thus, while
225
Ac is potentially useful in radioimmunotherapy, a suitable chelate is needed. Until now, a suitable chelate with sufficient in vivo stability had yet to be discovered. Certain bifunctional large cyclic chelate ligands are described in JP3-197468. However, there is no teaching or suggestion in JP3-197468 that the disclosed ligands would be useful to chelate
225
Ac. Accordingly, it is an object of the present invention to provide chelated
225
Ac. It is another object of the present invention to provide methods of synthesizing the chelate and related compounds. It is yet another object of the present invention to provide methods of using the chelate and related compounds. These and other objects, as well as additional advantages and inventive features, will become apparent from the detailed description provided herein.
BRIEF SUMMARY OF THE INVENTION
The present invention provides an &agr;-particle-emitting radioisotope chelation complex comprising
225
Actinium (
225
Ac) and 1,4,7,10,13,16-hexaazacyclooctodecane-N,N′,N″,N′″,N″″,N′″″-hexaacetic acid (HEHA) (
225
Ac-HEHA). Also provided is a bifunctional HEHA which can chelate a radiosotope, in particular
225
Ac, and can be attached to a targeting agent, such as a bifunctional HEHA having one of the following formulae:
wherein R is CO
2
H, CONHR′, P(O)R′OH or P(O) (OR′)CH, R′ is H, a C
1
-C
8
alkyl, phenyl or benzyl, wherein said phenyl or benzyl is unsubstituted or substituted, n is 1-6, X is NO
2
, NH
2
, NCS, NHC(O)CH
2
Z (in which Z is Cl, Br or I), or
Other bifunctional HEHAs are set forth herein. A compound comprising the bifunctional HEHA conjugated to a targeting agent is also provided. Accordingly, further provided is a bifunctional
225
Ac-HEHA complex comprising
225
Ac complexed with the bifunctional HEHA described above as well as a compound comprising the bifunctional
225
Ac HEHA complex conjugated to a targeting agent.
In view of the above, the present invention further provides a method of making HEHA. The method comprises preparing the free base of 1,4,7,10,13,16-hexaazacyclooctodecane under anhydrous conditions, azeotropically removing trace water with benzene, N-alkylating the macrocycle to produce the hexaester, saponifying the hexaester, and purifying HEHA. Preferably, the hexaester is produced by reacting the free base with Na
2
CO
3
and tert-butyl bromoacetate in anhydrous CH
3
CN.
Still further provided is a method of making a bifunctional HEHA. The method comprises the preparation of a tert-butyloxycarbonyl protected iminodiacetic acid that is condensed with an amino acid ester. The resulting diester is then saponified with base, and after acidification, converted to a disuccinimidyl ester. This active diester is then reacted with an N-2-aminoethyl amide of para-nitrophenylalanine that introduces the latent bifunctionality aspect that will be unmasked. The protecting group is removed by treatment with acid, and the amide carbonyl functional groups are reduced via diborane. The resulting macrocyclic polyamine is isolated as the protonated salt. The free base is generated and then the free amines are alkylated to introduce protected R groups. The protected R groups are then deprotected. The nitro group is then hydrogenated to the aniline, which is then converted to an isothiocyanate, a haloacetamide or a maleimide for conjugation to a targeting agent. The method can further comprise the conjugation of a bifunctional HEHA to a targeting agent. Alternatively, the method comprises the preparation of a cyclic hexapeptide that comprises para-nitrophenylalanine or &egr;-protected lysine and the subsequent reduction of amide carbonyl functional groups. The resulting macrocyclic polyamine is isolated as the protonated salt. The free base is then generated and the free amines are alkylated to introduce protected R groups, which are subsequently deprotected. The nitro group is hydrogenated to the aniline and the aniline is converted to an isothiocyanate, a haloacetamide or a maleimide, any one of which can then be conjugated to a targeting agent.
In another embodiment, a method of treating disease is provided. The method comprises administering to a patient having disease a disease-treatment effective amount of a
Brechbiel Martin W.
Deal Kim
Jones Dameron L.
Leydig , Voit & Mayer, Ltd.
The United States of America as represented by the Department of
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