Drug – bio-affecting and body treating compositions – Radionuclide or intended radionuclide containing; adjuvant... – In an organic compound
Reexamination Certificate
2001-04-20
2003-09-02
Hartley, Michael G. (Department: 1616)
Drug, bio-affecting and body treating compositions
Radionuclide or intended radionuclide containing; adjuvant...
In an organic compound
C534S010000, C534S014000
Reexamination Certificate
active
06613304
ABSTRACT:
FIELD OF THE INVENTION
The invention is in the field of diagnostic imaging and therapeutics. It relates to novel metal chelates containing metal species bound by 2-pyrrolylthione core in N
2
S
2
fashion. Methods for the preparation of the chelate complexes are provided. The invention also provides pharmaceutical compositions comprising the metal chelate, and the use of this composition as a diagnostic imaging or therapeutic agent. Kits comprising the compounds and compositions of the invention are also provided.
BACKGROUND OF THE RELATED ART
The art of diagnostic imaging employs contrasting agents that in binding or accumulating site-specifically within the body help to resolve the image of diagnostic interest.
For example, renography using radiotracers is the method of choice that allows the determination of both total and differential renal function and the detection of obstructions in urine flow. For this purpose, a composition comprising the radiopharmaceutical, such as an injectable liquid, is administered to the patient. By means of a suitable detection apparatus, such as a camera for detecting radiodecay, images can be obtained by recording the emitting radiation. Thus the organ or the pathological process in which the radiopharmaceutical has been incorporated may be visualized.
Among the oldest and most widely employed techniques for renal function evaluation are the renal clearance methods; the most fundamental of which is directed toward determination of glomerular filtration rate (GFR). In addition, the clearance of compounds that undergo extensive tubular excretion in addition to filtration allow the evaluation of functional tubular mass and the estimation of effective renal plasma flow (ERPF).
The standard for ERPF determination is p-aminohippurate (PAH), of which approxymately 90% is extracted from the renal arterial plasma in a single pass through the renal parenchyma. An I-131 labeled structural analog, ortho-iodohippurate ([
131
I]OIH; Hippuran), has been the clinical standard for the past 30 years. Although OIH yields a good approximation of renal plasma flow, the 364 keV photon energies of I-131 results in poor spatial resolution and the emission of beta partcles increases the radiation dose to the patient. Labeling OIH with I-123 results in a better imaging agent, but the availability and prohibitively high cost of I-123 limits the use of this compound.
Because of the favorable physical properties, widespread availability, and low cost of technetium-99m (Tc-99m), this radionuclide continues to be the most attractive candidate for the formulation of diagnostic radiopharmaceuticals to be used in scintigraphic gamma-imaging studies in patients (Jurisson et al., “Coordination compounds in nuclear medicine”.
Chem.Rev.
93:1137-1156 (1993)).
[
99m
Tc]TcO(glucoheptonate)
2
, Glucoscan, also known as Technescan, is an early kidney imaging agent, the precise structure of which has never been determined. While this complex is no longer widely used as an imaging agent; however, it is regularly used as a precursor for the synthesis of other Tc(V) species via ligand exchange.
[
99m
Tc]Tc-diethylenetriaminepentaacetic acid (or [
99m
Tc]Tc-DTPA) has received regulatory approval for use as a kidney imaging agent. The structure of this complex has not yet been determined unequivocally, and it is unclear as to whether the complex contains technetium in the IV or V oxidation state. This radiopharmaceutical has very limited clinical applications.
Early attempts to create a Tc-99m-based renal imaging agent focussed on the diamine dithiolate (DADT) ligands.
99m
Tc-N,N′-bis(mercaptoacetyl)-2,3-diaminopropanoate (
99m
Tc-CO
2
DADS) (Fritzberg et al., “Synthesis and biological evaluation of Tc-99m-N,N′-bis(mercaptoacetyl)-2,3-diaminopropanoate: A potential replacement for [I-131]-o-iodohippurate” 23:592-598 (1982)) has a favorable renal clearance profile, but this compound consists of stereoisomers with different rates and specificities for renal clearance. Therefore, HPLC separation of the desired stereoisomer is required, which makes routine preparation inconvenient.
The para-aminohippuric (PAH) acids have been found to be almost completely extracted from blood flow by the kidneys. Incorporation of an iminodiacetic acid (IDA) moiety into PAH yielded p-[(biscarboxymethylaminomethyl)carbamino]hippuric acid (PAHIDA) with a clearance of less than 50% of OIH (Chervu et al., “Technetium-99m labeled p-aminohippuric acid analog: A new renal agent”
J. Nucl. Med.
25:1111-1115 (1984)).
Later, the triamide mercaptide (N
3
S) class of Tc-99m-chelating agents was developed (Fritzberg et al., “Synthesis and biological evaluation of Tc-99m-MAG
3
as a hippuran replacement”
J. Nucl. Med.
27:111-116 (1986)). To date, the
99m
Tc-mercaptoacetyltriglycine ([
99m
TcO-MAG
3
]
−
) is considered to be one of the most successful agents for functional renal imaging. A few minutes post injection, approximately 1-2% of the injected dose of Tc-99m-MAG
3
is found in the kidneys. At the same time, this drug is cleared from the kidney tissue very rapidly. It is the passage into and through the kidneys that provides a measure of renal function (ERPF). Although considered to be the renal imaging agent of choice, Tc-99m-MAG
3
is not free of certain problems associated with its use. For instance, the plasma-protein binding of Tc-99m-MAG
3
is very high (Taylor et al.,
Radiology.
162:365-370 (1987); and Bubeck et al.,
J Nucl. Med.
31:1285-1293 (1990)); the clearance of Tc-99m-MAG
3
is only 50-60% of that of OIH and therefore is not suitable for direct measurement of ERPF. In addition, the preparation of Tc-99m-MAG
3
requires the kit to be heated at 100° C. for 10 min, thus adding an inconvenient step in the preparation.
It was found (Verbruggen et al., “Technetium and rhenium in chemistry and nuclear medicine”, vol.3 (M. Nicolini, G. Bandoli, U. Mazzi, eds.). Verona: Cortina International, pp. 445-452 (1990)) that the polar metabolite of the brain radiopharmaceutical, diethyl Tc-99m-ethylenedicysteine (Tc-99m-L,L-EC), was rapidly and efficiently excreted by the kidneys in mice. This observation prompted the evaluation of Tc-99m-L,L-EC as a potential renal imaging agent. Studies in mice and baboons showed that the pharmacokinetic properties of Tc-99m-L,L-EC are superior to those of Tc-99m-MAG
3
. Tc-99m-L,L-EC yields a better approximation of ERPF.
The true test of a new radiopharmaceutical, however, is how it performs in patients with various renal disorders that can cause drastic changes in pharmacokinetics. To date a number of clinical studies have been conducted in patients with a variety of renal disorders comparing Tc-99m-L,L-EC and Tc-99m-MAG
3
. Generally speaking, between the two tracers, there was no significant difference in the image quality or in the parameters derived from the renogram.
Because of the low chemical stability of the thiol group to oxidation, MAG
3
is synthesized and supplied in commercial kits as an S-benzyl protected derivative. After reconstitution the kit must be kept in the dark to prevent oxidation of the thiol.
To circumvent this problem, an attempt was made to substitute a hydroxy group for the thiol in MAG
3
(Vanbilloen et al., “Characteristics and biological behavior of Tc-99m-labeled hydroxyacetylglycine, a potential alternative to
99m
Tc-MAG
3
”.; Eur. J. Nucl. Med.
24:1374-1379 (1997)). The resulting Tc-99m-labeled hydroxyacetyltriglycine (HAG
3
) had a slightly higher urinary excretion and faster renal transit than Tc-99m-MAG
3
. The faster renal clearance of Tc-99m-HAG
3
can be attributed to its lower plasma protein binding—comparable with what was seen with Tc-99m-L,L-EC. Although the renal excretion characteristics of Tc-99m-HAG
3
are slightly better than those of Tc-99m-MAG
3
and the labeling is done at room temperature, the chemical stability of the Tc-99m-HAG
3
to transchelation is less than that of the thiol containing analog.
Certain Tc-99m-labeled molecules
Dolphin David H.
Kudrevich Svetlana V.
Rousseau Jacques
Selivanova Svetlana V.
Van Lier Johannes E.
Hartley Michael G.
Morrison & Foerster / LLP
University of British Columbia
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