Organic compounds -- part of the class 532-570 series – Organic compounds – Radioactive metal containing
Reexamination Certificate
2000-05-24
2002-03-19
Ceperley, Mary E. (Department: 1641)
Organic compounds -- part of the class 532-570 series
Organic compounds
Radioactive metal containing
C424S001570, C424S001650, C424S001690, C424S001730, C435S007240, C435S007250, C435S372000, C530S402000, C530S811000, C556S046000
Reexamination Certificate
active
06359119
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a novel method for preparing Mn, Tc and Re carbonyl complexes which are useful such as for imaging and therapeutic agents.
BACKGROUND OF THE INVENTION
Scintigraphic imaging and similar radiographic techniques for visualizing tissues in vivo are finding ever-increasing application in biological and medical research and in diagnostic and therapeutic procedures. Generally, scintigraphic procedures involve the preparation of radioactive agents which, upon introduction to a biological subject, become localized in the specific organ, tissue or skeletal structure of choice. When so localized, traces, plots or scintiphotos depicting the in vivo distribution of radiographic material can be made by various radiation detectors, e.g., traversing scanners and scintillation cameras. The distribution and corresponding relative intensity of the detected radioactive material not only indicates the space occupied by the targeted tissue, but also indicates a presence of receptors, antigens, aberrations, pathological conditions, and the like.
Technetium-99m (
99m
Tc) is a radionuclide which is widely known for its uses in tissue imaging agents. Due to its safety and ideal imaging properties, this radionuclide is conveniently available commercially in the oxidized pertechnetate form (
99m
TcO
4
−
) hereinafter “pertechnetate-Tc99m”. However, pertechnetate will not complex with the most commonly used biological carriers for radionuclide tissue imaging. Thus, technetium-labeled imaging agents are generally prepared by admixing a pertechnetate-Tc99m isotonic saline solution, a technetium reductant (reducing agent) such as stannous chloride or sodium dithionite, and a chelate conjugated to the desired peptide carrier agent for targeting the organ of interest. Alternatively, an intermediate transfer liquid-technetium 99m complex may be prepared prior to addition to the chelate-biological molecule to maintain the oxidation state within a desired level. Examples of such include
99m
Tc-tartrate or
99m
Tc-gluconate.
Another problem is that technetium-containing scintigraphic imaging agents are known to be unstable in the presence of oxygen, primarily since oxidation of the reductant and/or the technetium-99m destroys the reduced technetium-99m/targeting carrier complex. Accordingly, such imaging agents are generally made oxygen-free by saturating the compositions with oxygen-free nitrogen gas or by preparing the agents in an oxygen-free atmosphere. Stabilization of imaging agents can also be achieved through chemical means. U.S. Pat. No. 4,232,000, Fawzi, issued Nov. 4, 1980, discloses the use of gentisyl alcohol as a stabilizer for technetium imaging agents. Similarly, U.S. Pat. No. 4,233,284, Fawzi, issued Nov. 11, 1980, discloses the use of gentisic acid as a stabilizer.
In published PCT Application No. PCT/US98/07979 (International Publication No. WO 98/48848), which is incorporated herein in its entirety by reference, a method was disclosed for preparing a compound of the general formula (I): fac-[M(CO)
3
(OH
2
)
3
]
+
wherein M is Mn,
99m
Tc,
186
Re or
188
Re, by reacting a metal in the permetallate form with carbon monoxide and a reducing agent, characterized in that a mixture of a base, a reducing agent soluble in water but not substantially decomposed by water, and optionally a stabilizing agent is dissolved in a water containing solvent system containing a solution of the metal in the permanganate, pertechnetate or perrhenate form in the presence of carbon monoxide and optionally in the presence of a halide. The ligands disclosed for labeling biologically active molecules have a tendency to stabilize metals in their low oxidation states. These ligands have in common the presence of low-lying vacant orbitals of the correct symmetry to form pi-bonds by accepting electrons from filled metal d-orbitals, a phenomenon known as backbonding. The ligands indicated in the patent application include isonitriles, phosphines, thioethers, Schiff bases, and pyridine-, imidazole-, and pyrazole-type groups. In particular, the amino acid histidine is indicated as an ideal chelate. For some purposes a problem with using histidine and other unsaturated organic molecules as chelates is that the resulting labeled compound is highly lipophilic resulting in high liver and blood uptake. The predominant hepatobiliary uptake and clearance are for some purposes undesirable characteristics for the targeted imaging agents.
The publications and other materials used herein to illuminate the background of the invention or provide additional details respecting the practice, are incorporated by reference, and for convenience are respectively grouped in the appended List of References.
SUMMARY OF THE INVENTION
In accordance with the present invention, a method of preparing a compound of formula
fac-[M(CO)
3
(OH
2
)
3
]
+
(I)
wherein M is Mn,
99m
Tc,
186
Re or
188
Re,
involves reacting a metal in permetallate form with carbon monoxide and a reducing agent, wherein the reducing agent comprises a stannous ion. The compound of formula (I) can be reacted with a ligand L
x
to form a compound of the formula
fac-[M(CO)
3
L
x
]
n
(II)
wherein M is as defined above, L
x
is a monodentate or multidentate ligand or a mixture of these ligands, and n is a charge of the ligand L
x
increased with one + charge. The invention also is directed to kits for performing the disclosed methods.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to an improved method for synthesizing Tc(I) complexes using stannous ion as the reducing agent. For formulating Tc(I) complexes, e.g., [Tc(CO)
3
(OH
2
)
3
]
30
, the prior art methods have successfully used only the powerful reductants of borohydrides (BH
3
or BH
4
−
). Attempts to use other reductants including stannous ion (Sn
2+
) have resulted in labeling yields of approximately only 50%. The use of the more common Sn
2+
in radiopharmaceutical kits has certain advantages such as a wide pH range of use, known toxicity, familiarity with the FDA and perhaps better adaptability between Tc and Re formulations. In addition, stannous ion is less likely to interfere with the biological substrate or ligands which are ultimately labeled. The instant invention discloses a method of using Sn
2+
for the preparation of Tc-carbonyl complexes with yields of >80%, a clear improvement of the previous work.
It has normally been felt that to form Tc in oxidation state I as is the case of the Tc-carbonyl complexes formed according to this disclosure, a very strong reductant is needed, one with a negative value in the electrochemical series. The starting Tc compound is pertechnetate, TcO
4
−
, which has Tc in oxidation state VII. To form the desired Tc-carbonyl complexes, it is necessary to reduce the Tc(VII) down to Tc(I).
Stannous ion is normally not thought of as a strong reductant because its electrochemical half equation is not very negative. In the presence of a 0.1 N acid, the electrochemical equation is:
Sn
4+
+2e
−
⇄Sn
2+
E°=+0.15 Volts
The effect of pH upon this equation is usually forgotten. At a basic pH (>7) the reducing strength of stannous ion is changed as a result of a change in the reductant's mechanism. In a basic solution, a stannous hydroxide chemical species is present with a different mechanism and reductant strength which is capable of reducing the Tc(VII) down to Tc(I), especially with the aid of an appropriate transfer ligand such as pyrophosphate or another ligand such as tartrate, gluceptate, methylenediphosphonate or hydroxyethyldiphosphonate. In a basic solution (0.1 N NaOH, pH=13), the half equation is:
Sn(OH)
6
2−
+2e
−
⇄HSnO
2
−
+3OH
−
+H
2
O E°=−0.96 Volt
This shows that stannous ion is a strong reductant at a basic pH. This is comparable to the electrochemical half equation for borohydrid
Dyszlewski Mary E.
Pipes David W.
Webb Elizabeth G.
Ceperley Mary E.
Mallinckrodt Inc.
Rothwell Figg Ernst & Manbeck
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