CHELATOR INCORPORATED ARG-GLY-ASP (RGD) MIMETIC SYNTHETIC DISINTEGRINS AS IMAGING AGENTS

Abstract: The present invention describes novel compounds of formula (I) wherein R<1>, R<2>, R<3>, R<4>, and n are as defined herein, which act as antagonists of the platelet glycoprotein IIb/IIIa complex, <99m>Tc labeled radiopharmaceuticals made therefrom, methods of using the same as imaging agents for the diagnosis of arterial and venous thrombi, and kits comprising the same.

Description: TITLE Chelator Incorporated Arg-Gly-Asp (RGD) Mimetic Synthetic Disintegrins As Imaging Agents FIELD OF THE INVENTION This invention relates to novel radiopharmaceuticals that are radiolabeled chelator incorporated RGD mimetic synthetic disintegrins, methods of using the same as imaging agents for the diagnosis of arterial and venous thrombi, and novel reagents for the preparation of the same and kits comprising the reagents. BACKGROUND OF THE INVENTION The clinical recognition of venous and arterial thromboembolic disorders is unreliable, lacking in both sensitivity and specificity. In light of the potentially life threatening situation, the need to rapidly diagnose thromboembolic disorders using a non-invasive method is an unmet clinical need. Platelet activation and resulting aggregation has been shown to be associated with various pathophysiological conditions including cardiovascular and cerebrovascular thromboembolic disorders such as unstable angina, myocardial infarction, transient ischemic attack, stroke, atherosclerosis and diabetes. The contribution of platelets to these disease processes stems from their ability to form aggregates, or platelet thrombi, especially in the arterial wall following injury. See generally, Fuster et al . , J. Am. Coll. Cardiol., Vol. 5, No. 6, pp. 175B-183B (1985); Rubenstein et al . , Am. Heart J. , Vol. 102, pp. 363-367 (1981); Hamm et al . , J. Am. Coll. Cardiol., Vol. 10, pp. 998-1006 (1987); and Davies et al . , Circulation, Vol. 73, pp. 418-427 (1986). Recently, the platelet glycoprotein Ilb/IIIa complex (GPIIb/IIIa) , has been identified as the membrane protein which mediates platelet aggregation by providing a common pathway for the known platelet agonists. See Philips et al . , Cell, Vol. 65, pp. 359-362 (1991) . Platelet activation and aggregation is also thought to play a significant role in venous thromboembolic disorders such as venous thrombophlebitis and subsequent pulmonary emboli. It is also known that patients whose blood flows over artificial surfaces, such as prosthetic synthetic cardiac valves, are at risk for the development of platelet plugs, thrombi and emboli. See generally Fuster et al . , J. Am. Coll. Cardiol., Vol. 5, No. 6, pp. 175B-183B (1985); Rubenstein et al . , Am. Heart J. , Vol. 102, pp. 363-367 (1981); Hamm et al . , J. Am. Coll. Cardiol., Vol. 10, pp. 998-1006 (1987); and Davies et al . , Circulation, Vol. 73, pp. 418-427 (1986) . A suitable means for the non-invasive diagnosis and monitoring of patients with such potential thromboembolic disorders would be highly useful, and several attempts have been made to develop radiolabeled agents targeted to platelets for non-invasive radionuclide imaging. For example, experimental studies have been carried out with 99mTc monoclonal antifibrin antibody for diagnostic imaging of arterial thrombus. See Cerqueira et al . , Circulation, Vol., 85, pp. 298-304 (1992). The authors report the potential utility of such agents in the imaging of freshly formed arterial thrombus . Monoclonal antibodies labeled with 1311 and specific for activated human platelets have also been reported to have potential application in the diagnosis of arterial and venous thrombi. However, a reasonable ratio of thrombus to blood (target/background) was only attainable at 4 hours after the administration of the radiolabeled antibody. See Wu et al . , Clin. Med. J. , Vol. 105, pp. 533-559 (1992). The use of 1251, 1311, 99mTc, and lllln radiolabeled 7E3 monoclonal antiplatelet antibody in imaging thrombi has also been recently discussed. Coller et al., PCT Application Publication No. WO 89/11538 (1989). The radiolabeled 7E3 antibody has the disadvantage, however, of being a very large molecular weight molecule. Other researchers have employed enzymatically inactivated t-PA radioiodinated with 1231, 1251 and 1311 for the detection and the localization of thrombi. See Ordm et al . , Circulation, Vol. 85, pp. 288-297 (1992). Still other approaches in the radiologic detection of thromoboembolisms are described, for example, in Koblik et al . , Semin. Nucl. Med., Vol. 19, pp. 221-237 (1989). Arterial and venous thrombus detection and localization is of critical importance in accurately diagnosing thromboembolic disorders and determining proper therapy. New and better radiolabeled agents for non-invasive radionuclide imaging to detect thrombi are needed. The present invention is directed to this important end. SUMMARY OF THE INVENTION Accordingly, one object of the present invention is to provide novel compounds for making radiopharmaceuticals which act as antagonists of the platelet glycoprotein Ilb/IIIa complex. It is another object of the present invention is to provide novel radiopharmaceuticals which act as antagonists of the platelet glycoprotein Ilb/IIIa complex. It is another object of the present invention is to provide a method of using said radiopharmaceuticals as imaging agents for the diagnosis of arterial and venous thrombi . It is another object of the present invention to provide novel radiopharmaceutical compositions for the diagnosis of arterial and venous thrombi. It is another object of the present invention to provide novel kits comprising the compounds of the present invention for making radiopharmaceutical compositions. These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors' discovery that compounds of formula (I) : (I) or a pharmaceutically acceptable salt or prodrug form thereof, wherein n, R 1 , R 2 , R 3 and R 4 are as defined below, are effective reagents for making radiopharmaceuticals which act as antagonists of the platelet glycoprotein Ilb/IIIa complex. DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS [1] Thus, in a first embodiment, the present invention provides a novel compound of formula (I) : (I) or a pharmaceutically acceptable salt form thereof, wherein: R 1 is selected from the group H and NH 2 ; R 2 is selected from the group CH 2 C0 2 H and CH 2 CH 2 C0 2 H; R 3 is selected from the group: wherein * indicates where R 3 is attached to formula I; R 4 is selected from the group CH 2 NHC ( =NH) NH 2 , NHC(=NH)NH 2 , C(=NH)NH 2 , CH 2 C(=NH)NH 2 , and CH 2 CH 2 C (=NH) NH 2 ; and n is 0 or 1. [2] In a preferred embodiment, the present invention provides a novel compound wherein; R 4 is NHC(=NH)NH 2 . [3] In a more preferred -embodiment , the present invention provides a novel compound wherein; R 1 is NH 2 ; R 2 is CH 2 C0 2 H; wherein * indicates where R 3 is attached to formula I; and, n is 0. [4] In another more preferred embodiment, the present invention provides a novel compound wherein; R 1 is H; R 2 is CH 2 C0 2 H; wherein * indicates where R 3 is attached to formula I; and, n is 0. [5] In another more preferred embodiment, the present invention provides a novel compound wherein; R 1 is NH 2 ; R 2 is CH 2 C0 2 H; wherein * indicates where R 3 is attached to formula I; and, n is 1. [6] In another more preferred embodiment, the present invention provides a novel compound wherein; R 1 is NH 2 ; R 2 is CH C0 2 H; wherein * indicates where R 3 is attached to formula I; and, n is 0. [7] In another more preferred embodiment, the present invention provides a novel compound wherein; R 1 is H ; R 2 is CH 2 C0 2 H ; wherein * indicates where R 3 is attached to formula I; and, n is 0. [8] In a second embodiment, the present invention provides a novel kit for preparing a radiopharmaceutical comprising a predetermined quantity of a compound of formula (I) or a pharmaceutically acceptable salt form thereof. [9] In a third embodiment, the present invention provides a novel radiopharmaceutical comprising a complex of a compound of formula (I) and 99 m Tc. [10] In a fourth embodiment, the present invention provides a novel radiopharmaceutical composition comprising a radiopharmaceutically acceptable carrier and a 99ιrι Tc labeled compound of formula (I) . [11] In a fifth embodiment, the present invention provides a novel method of imaging, comprising: (i) administering to said mammal an effective amount of a 99m r c labeled compound of formula (I) , and (ii) imaging the mammal. [12] In another preferred embodiment, the method of imaging is for visualizing sites of platelet deposition in a mammal. [13] In another preferred embodiment, the method of imaging is for determining platelet deposition in a mammal. [14] In another preferred embodiment, the method of imaging is for diagnosing a disorder associated with platelet deposition in a mammal. [15] In a sixth embodiment, the present invention provides a novel sterile, non-pyrogenic kit for radioimaging a mammal, comprising: (a) a predetermined quantity of a compound of formula (I) ; and, (b) a predetermined quantity of a reducing agent. [16] In another preferred embodiment, components (a) and (b) are contained in a vial. [17] In another preferred embodiment, component (a) is contained in a first vial and component (b) is contained in a second vial. [18] In another preferred embodiment, the reducing agent is stannous chloride. DEFINITIONS As noted above, the compounds of the present invention may be radiolabeled. By "radiolabeled", it is meant that the subject platelet glycoprotein Ilb/IIIa compounds contain a radioisotope which is suitable for administration to a mammalian patient The terms "metal chelator" and "chelator" are used interchangeably throughout to designate a chemical moiety capable of binding to or complexing with a metal nuclide. As discussed below, the platelet glycoprotein Ilb/IIIa compounds of the present invention may be radiolabeled by incorporating the radiolabel into the compounds through a chelating agent, where the chelating agent has been incorporated into the compounds. In formula (I), the metal chelator is intended to be the group: It has been discovered that the radiolabeled compounds of the invention may be useful as radiopharmaceuticals for non-invasive imaging to diagnose present or potential thromboembolic disorders, such as arterial or venous thrombosis, including, for example, unstable angina, myocardial infarction, transient ischemic attack, stroke, atherosclerosis, diabetes, thrombophlebitis, pulmonary emboli, platelet plugs, and thrombi or emboli caused by prosthetic cardiac devices such as heart valves . The radiolabeled compounds of the invention may be useful with both newly formed and older thrombi . The radiolabeled compounds of the invention may also be used to diagnose other present or potential conditions where there is overexpression of the GPIIb/IIIa receptors, such as with metastatic cancer cells. The subject compounds may be effectively employed in low doses, thereby minimizing any risk of toxicity. Also, the subject compounds are of a much smaller size than, for example, the radiolabeled 7E3 antibodies known in the art, allowing easier attainment of suitable target/background (T/B) ratio for detecting thrombi. The use of the radiolabeled compounds of the invention is further described in the utility section below. A "diagnostic kit," as used herein, comprises a collection of components, termed the formulation, in one or more vials which are used by the practising end user in a clinical or pharmacy setting to synthesize the radiopharmaceutical. The kit provides all the requisite components to synthesize and use the radiopharmaceutical except those that are commonly available to the practising end user, such as water or saline for injection, a solution of the radionuclide, equipment for heating the kit during the synthesis of the radiopharmaceutical if required, equipment necessary for administering the radiopharmaceutical to the patient such as syringes and shielding, and imaging equipment. The present kits may be contained in one or more vials and all or part of the formulation can independently be in the form of a sterile solution or a lyophilized solid. It is preferred that reagent and reducing agent be lyophilized, when possible, to facilitate storage stability. If lyophilization is not practical, the kits can be stored frozen or in solution at room temperature. The solvents used are usually water or saline, preferably, water. Preferably, the kits are sealed. A "buffer, " as used herein, is a compound that is used to control the pH of the kit during its manufacture and during the synthesis of the radiopharmaceutical. A "lyophilization aid, " as used herein, is a component that has favorable physical properties for lyophilization, such as the glass transition temperature, and is added to the diagnostic kit to improve the physical properties of the combination of all the components of the kit for lyophilization . A "stabilization aid," as used herein, is a component that is added to the radiopharmaceutical or to the diagnostic kit either to stabilize the radiopharmaceutical once it is synthesized or to prolong the shelf-life of the kit before it must be used. Stabilization aids can be antioxidants, reducing agents or radical scavengers and can provide improved stability by reacting preferentially with species that degrade other components or the radiopharmaceutical . A "solubilization aid," as used herein, is a component that improves the solubility of one or more other components in the medium required for the synthesis of the radiopharmaceutical. A "bacteriostat, " as used herein, is a component that inhibits the growth of bacteria in the diagnostic kit either during its storage before use of after the kit is used to synthesize the radiopharmaceutical. A "reducing agent, " as used herein, is a compound that reacts with the radionuclide, which is typically obtained as a relatively unreactive, high oxidation state compound, to lower its oxidation state by transfering electron (s) to the radionuclide, thereby making it more reactive. Reducing agents useful in the preparation of radiopharmaceuticals and in diagnostic kits useful for the preparation of said radiopharmaceuticals include but are not limited to stannous chloride, stannous fluoride, formamidine sulfinic acid, ascorbic acid, cysteine, phosphines, and cuprous or ferrous salts. Other reducing agents are described in Brodack et. al . , PCT Application 94/22496, which is incorporated herein by reference. A "transfer ligand, " as used herein, is a ligand that forms an intermediate complex with the radionuclide that is stable enough to prevent unwanted side-reactions but labile enough to be converted to the radiopharmaceutical . The formation of the intermediate complex is kinetically favored while the formation of the radiopharmaceutical is thermodynamically favored. Transfer ligands useful in the preparation of radiopharmaceuticals and in diagnostic kits useful for the preparation of said radiopharmaceuticals include but are not limited to gluconate, glucoheptonate, mannitol, glucarate, N,N, N' ,N' -ethylenediaminetetraacetic acid, pyrophosphate and methylenediphosphonate . In general, transfer ligands are comprised of oxygen or nitrogen donor atoms . The compounds herein described may have asymmetric centers. Unless otherwise indicated, all chiral, diastereomeric and racemic forms are included in the present invention. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. It will be appreciated that compounds of the present invention contain asymmetrically substituted carbon atoms, and may be isolated in optically active or racemic forms . It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Two distinct isomers (cis and trans) of the peptide bond are known to occur; both can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Unless otherwise specifically noted, the L-isomer (or equivalent R or S configuration) of the amino acid is preferably used at all positions of the compounds of the present invention. Except as provided in the preceding sentence, all chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomer form is specifically indicated. The D and L-isomers of a particular amino acid are designated herein using the conventional 3 -letter abbreviation of the amino acid, as indicated by the following examples: D-Leu or L-Leu. Pg is selected from a variety of thiol protecting groups capable of being displaced upon reaction with a radionuclide, or deprotected under the reaction (radiolabeling) conditions. Such thiol protecting groups include those listed in Greene and Wuts, "Protective Groups in Organic Synthesis" John Wiley & Sons, New York (1991) , the disclosure of which is hereby incorporated by reference. Any thiol protecting group known by those skilled in the art can be used. Examples of preferred thiol protecting groups include the following: acetamidomethyl (ACM) , 1-ethoxyethyl (EOE) , p-anisylidene, tetrahydropyranyl (THP) , tetrahydrofuranyl (THF) , and derivatives thereof. As used herein, the term "amine protecting group" means any group known in the art of organic synthesis for the protection of amine groups . Such amine protecting groups include those listed in Greene and Wuts, "Protective Groups in Organic Synthesis" John Wiley & Sons, New York (1991) and "The Peptides: Analysis, Sythesis, Biology, Vol. 3, Academic Press, New York (1981) , the disclosure of which is hereby incorporated by reference. Any amine protecting group known in the art can be used. Examples of amine protecting groups include, but are not limited to, the following: 1) acyl types such as formyl, trifluoroacetyl, phthalyl, and p-toluenesulfonyl; 2) aromatic carbamate types such as benzyloxycarbonyl (Cbz or Z) and substituted benzyloxycarbonyls , 1- (p-biphenyl ) -1-methylethoxycarbonyl , and 9-fluorenylmethyloxycarbonyl (Fmoc) ; 3) aliphatic carbamate types such as tert-butyloxycarbonyl (Boc) , ethoxycarbonyl , diisopropylmethoxycarbonyl , and allyloxycarbonyl; 4) cyclic alkyl carbamate types such as cyclopentyloxycarbonyl and adamantyloxycarbonyl ; 5) alkyl types such as triphenylmethyl and benzyl; 6) trialkylsilane such as trimethylsilane; and 7) thiol containing types such as phenylthiocarbonyl and dithiasuccinoyl . Also included in the term "amine protecting group" are acyl groups such as azidobenzoyl, p-benzoylbenzoyl, o-benzylbenzoyl, p- acetylbenzoyl, dansyl, glycyl-p-benzoylbenzoyl, phenylbenzoyl, m-benzoylbenzoyl , benzoylbenzoyl . The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; and alkali or organic salts of acidic residues such as carboxylic acids. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non- toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pa oic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington 's Pharmaceutical Sciences, 17th ed. , Mack Publishing Company, Easton, PA, 1985, p. 1418, the disclosure of which is hereby incorporated by reference . Since prodrugs are known to enhance numerous desirable qualities of pharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc..) the compounds of the present invention may be delivered in prodrug form. Thus, the present invention is intended to cover prodrugs of the presently claimed compounds, methods of delivering the same and compositions containing the same. "Prodrugs" are intended to include any covalently bonded carriers which release an active parent drug of the present invention in vivo when such prodrug is administered to a mammalian subject. Prodrugs the present invention are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of the present invention wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug of the present invention is administered to a mammalian subject, it cleaves to form a free hydroxyl , free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of the present invention. The term "amino acid" as used herein means an organic compound containing both a basic amino group and an acidic carboxyl group. Included within this term are modified and unusual amino acids, such as those disclosed in, for example, Roberts and Vellaccio (1983) The Peptides, 5: 342- 429, the teaching of which is hereby incorporated by reference. Modified or unusual amino acids which can be used to practice the invention include, but are not limited to, D-amino acids, hydroxylysine, 4-hydroxyproline, ornithine, 2 , 4-diaminobutyric acid, 2 , 3-diaminopropionic acid, beta-2-thienylalanine, 4-aminophenylalanine, homoarginine , norleucine, N-methylaminobutyric acid, naphthylalanine, phenylglycine, β-phenylproline, tert-leucine, 4-aminocyclohexylalanine, N-methyl-norleucine, 3 , 4-dehydroproline, 4-aminopiperidine-4-carboxylic acid, 6- aminocaproic acid, trans-4- (aminomethyl) - cyclohexanecarboxylic acid, 2-, 3-, and 4- (aminomethyl) - benzoic acid, 1-aminocyclopentanecarboxylic acid, 1-aminocyclopropanecarboxylic acid, and 2-benzyl-5- aminopentanoic acid. The term "amino acid residue" as used herein means that portion of an amino acid (as defined herein) that is present in a peptide. The term "peptide" as used herein means a linear compound that consists of two or more amino acids (as defined herein) that are linked by means of a peptide bond. The term "peptide" also includes compounds containing both peptide and non-peptide components , such as pseudopeptide or peptide mimetic residues or other non-amino acid components. Such a compound containing both peptide and non-peptide components may also be referred to as a "peptide analog" . The following abbreviations are used herein: Acm acetamidomethyl β-Ala , beta-Ala or bAla 3-aminopropionic acid Boc t-butyloxycarbonyl Bzl benzyl CBZ, Cbz or Z Carbobenzyloxy Dap 2 , 3-diaminopropionic acid DCC dicyclohexylcarbodiimide DIEA or DIPEA diisopropylethylamine DMAP 4-dimethylaminopyridine DMF dimethylformamide EOE ethoxyethyl HBTU 2-(lH-Benzotriazol-l-yl)-l,l,3,3- tetramethyluronium hexafluorophosphate NMeArg or MeArg α-N-methyl arginine NMeAsp α-N-methyl aspartic acid NMM N-methylmorpholine OcHex 0-eye1ohexy1 OBzl O-benzyl oSu O-succinimidyl TBTU 2- (lH-Benzotriazol-1-yl) -1,1,3,3- tetramethyluronium tetrafluoroborate TFA trifluoroacetic acid TFMSA trifluoromethane sulfonic acid THF tetrahydrofuranyl THP tetrahydropyranyl Tos tosyl Tr trityl Generally, peptides are elongated by deprotecting the α-amine of the C-terminal residue and coupling the next suitably protected amino acid through a peptide linkage using the methods described. This deprotection and coupling procedure is repeated until the desired sequence is obtained. This coupling can be performed with the constituent amino acids in a stepwise fashion, or condensation of fragments (two to several amino acids) , or combination of both processes, or by solid phase peptide synthesis according to the method originally described by Merrifield, J. Am. Chem. Soc . , 85, 2149-2154 (1963), the disclosure of which is hereby incorporated by reference. The compounds of the invention may also be synthesized using automated peptide synthesizing equipment. In addition to the foregoing, procedures for peptide synthesis are described in Stewart and Young, "Solid Phase Peptide Synthesis", 2nd ed, Pierce Chemical Co., Rockford, IL (1984); Gross, Meienhofer, Udenfriend, Eds., "The Peptides : Analysis, Synthesis, Biology, Vol. 1, 2, 3, 5, and 9, Academic Press, New York, (1980-1987); Bodanszky, "Peptide Chemistry: A Practical Textbook", Springer-Verlag, New York (1988); and Bodanszky et al . "The Practice of Peptide Sythesis" Springer-Verlag, New York (1984) , the disclosures of which are hereby incorporated by reference. The coupling between two amino acid derivatives, an amino acid and a peptide, two peptide fragments, or the cyclization of a peptide can be carried out using standard coupling procedures such as the azide method, mixed carbonic acid anhydride (isobutyl chloroformate) method, carbodiimide (dicyclohexylcarbodiimide, diisopropylcarbodiimide, or water-soluble carbodiimides) method, active ester (p- nitrophenyl ester, N-hydroxysuccinic imido ester) method, Woodward reagent K method, carbonyldiimidazole method, phosphorus reagents such as BOP-Cl, or oxidation-reduction method. Some of these methods (especially the carbodiimide) can be enhanced by the addition of 1-hydroxybenzotriazole . These coupling reactions may be performed in either solution (liquid phase) or solid phase. The functional groups of the constituent amino acids must be protected during the coupling reactions to avoid undesired bonds being formed. The protecting groups that can be used are listed in Greene, "Protective Groups in Organic Synthesis" John Wiley & Sons, New York (1981) and "The Peptides: Analysis, Sythesis, Biology, Vol. 3, Academic Press, New York (1981) , the disclosure of which is hereby incorporated by reference. The α-carboxyl group of the C-terminal residue is usually protected by an ester that can be cleaved to give the carboxylic acid. These protecting groups include: 1) alkyl esters such as methyl and t-butyl, 2) aryl esters such as benzyl and substituted benzyl, or 3) esters which can be cleaved by mild base treatment or mild reductive means such as trichloroethyl and phenacyl esters . In the solid phase case, the C-terminal amino acid is attached to an insoluble carrier (usually polystyrene) . These insoluble carriers contain a group which will react with the carboxyl group to form a bond which is stable to the elongation conditions but readily cleaved later. Examples of which are: oxime resin (DeGrado and Kaiser (1980) J. Org. Chem. 45, 1295-1300) chloro or bromomethyl resin, hydroxymethyl resin, and aminomethyl resin. Many of these resins are commercially available with the desired C-terminal amino acid already incorporated . The α-amino group of each amino acid must be protected. Any protecting group known in the art can be used. Examples of these are: 1) acyl types such as formyl, trifluoroacetyl, phthalyl, and p-toluenesulfonyl; 2) aromatic carbamate types such as benzyloxycarbonyl (Cbz) and substituted benzyloxycarbonyIs , 1- (p-biphenyl) -1-methylethoxycarbonyl , and 9-fluorenylmethyloxycarbonyl (Fmoc) ; 3) aliphatic carbamate types such as tert-butyloxycarbonyl (Boc) , ethoxycarbonyl, diisopropylmethoxycarbonyl , and allyloxycarbonyl; 4) cyclic alkyl carbamate types such as cyclopentyloxycarbonyl and adamantyloxycarbonyl; 5) alkyl types such as triphenylmethyl and benzyl; 6) trialkylsilane such as trimethylsilane; and 7) thiol containing types such as phenylthiocarbonyl and dithiasuccinoyl . The preferred α-amino protecting group is either Boc or Fmoc. Many amino acid derivatives suitably protected for peptide synthesis are commercially available. The α-amino protecting group is cleaved prior to the coupling of the next amino acid. When the Boc group is used, the methods of choice are trifluoroacetic acid, neat or in dichloromethane, or HC1 in dioxane. The resulting ammonium salt is then neutralized either prior to the coupling or in situ with basic solutions such as aqueous buffers, or tertiary amines in dichloromethane or dimethylformamide. When the Fmoc group is used, the reagents of choice are piperidine or substituted piperidines in dimethylformamide, but any secondary amine or aqueous basic solutions can be used. The deprotection is carried out at a temperature between 0 °C and room temperature. Any of the amino acids bearing side chain functionalities may be protected during the preparation of the peptide using any of the above-identified groups. Those skilled in the art will appreciate that the selection and use of appropriate protecting groups for these side chain functionalities will depend upon the amino acid and presence of other protecting groups in the peptide. The selection of such a protecting group is important in that it must not be removed during the deprotection and coupling of the α-amino group . For example, when Boc is chosen for the α-amine protection the following protecting groups are acceptable: p-toluenesulfonyl (tosyl) moieties and nitro for arginine; benzyloxycarbonyl , substituted benzyloxycarbonyls, tosyl or trifluoroacetyl for lysine; benzyl or alkyl esters such as cyclopentyl for glutamic and aspartic acids; benzyl ethers for serine and threonine; benzyl ethers, substituted benzyl ethers or 2-bromobenzyloxycarbonyl for tyrosine; p- methylbenzyl , p-methoxybenzyl, acetamidomethyl, benzyl, or t-butylsulfonyl for cysteine; and the indole of tryptophan can either be left unprotected or protected with a formyl group . When Fmoc is chosen for the α-amine protection usually tert-butyl based protecting groups are acceptable . For instance, Boc can be used for lysine, tert-butyl ether for serine, threonine and tyrosine, and tert-butyl ester for glutamic and aspartic acids. When a solid phase synthesis is used, the peptide should be removed from the resin without simultaneously removing protecting groups from functional groups that might interfere with the cyclization process. Thus, if the peptide is to be cyclized in solution, the cleavage conditions need to be chosen such that a free α-carboxylate and a free α-amino group are generated without simultaneously removing other protecting groups. Alternatively, the peptide may be removed from the resin by hydrazinolysis, and then coupled by the azide method. Another very convenient method involves the synthesis of peptides on an oxime resin, followed by intramolecular nucleophilic displacement from the resin, which generates a peptide (Osapay, Profit, and Taylor (1990) Tetrahedron Letters 43, 6121-6124) . When the oxime resin is employed, the Boc protection scheme is generally chosen. Then, the preferred method for removing side chain protecting groups generally involves treatment with anhydrous HF containing additives such as dimethyl sulfide, anisole, thioanisole, or p-cresol at 0 °C. The cleavage of the peptide can also be accomplished by other acid reagents such as trifluoromethanesulfonic acid/trifluoroacetic acid mixtures. Unusual amino acids used in this invention can be synthesized by standard methods familiar to those skilled in the art ("The Peptides: Analysis, Sythesis, Biology, Vol. 5, pp. 342-449, Academic Press, New York (1981)). N-Alkyl amino acids can be prepared using procedures described in previously (Cheung et al . , (1977) Can . J. Chem . 55, 906; Freidinger et al . , (1982) J. Org . Chem . 48, 77 (1982)), which are incorporated here by reference. The compounds of the present invention may be prepared using the procedures further detailed below. Representative materials and methods that may be used in preparing the compounds of the invention are described further below. Manual solid phase peptide synthesis was performed in 25 rriL polypropylene filtration tubes purchased from BioRad Inc., or in 60 mL hour-glass reaction vessels purchased from Peptides International. Oxime resin (substitution level = 0.96 mmol/g) was prepared according to published procedures (DeGrado and Kaiser (1980) J. Org. Chem . 45, 1295), or was purchased from Novabiochem (substitution level = 0.62 mmol/g) . All chemicals and solvents (reagent grade) were used as supplied from the vendors cited without further purification. t-Butyloxycarbonyl (Boc) amino acids and other starting amino acids may be obtained commercially from Bachem Inc., Bachem Biosciences Inc. (Philadelphia, PA), Advanced ChemTech (Louisville, KY) , Peninsula Laboratories (Belmont, CA) , or Sigma (St. Louis, MO). 2-(lH- Benzotriazol-1-yl) -1,1,3, 3-tetramethyluronium hexafluorophosphate (HBTU) and TBTU were purchased from Advanced ChemTech. N-methylmorpholine (NMM) , m-cresol , D- 2-aminobutyric acid (Abu) , trimethylacetylchloride, diisopropylethylamine (DIEA) were purchased from Aldrich Chemical Company. Dimethylformamide (DMF) , ethyl acetate, chloroform (CHCI3), methanol (MeOH) , pyridine and hydrochloric acid (HCl) were obtained from Baker. Acetonitrile, dichloromethane (DCM) , acetic acid (HOAc) , trifluoroacetic acid (TFA) , ethyl ether, triethylamine, acetone, and magnesium sulfate were commercially obtained. Absolute ethanol was obtained from Quantum Chemical Corporation. Other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments which are given for illustration fo the invention and are not intended to be limiting thereof. EXAMPLES Example 1 Preparation of 3 - (3 - ( (4- (amidinoamino) phenyl ) carbonylamino) - 2-aminopropanoylamino) -3- (N- (2- thienylmethyl ) carbamoyl ) propanoic acid H-Boc Aminomethyl-thiophene coupled with Boc-Asp (OBzl) -OH (2.27 mmoles, 0.95 g) was deprotected using TFA (10 mL) in CH 2 C1 2 (10 mL) . The reaction mixture was stirred for 2 hr and thereupon concentrated to an oil. Three additional 20 mL aliquots of CH 2 C1 2 wash was performed to remove any traces of TFA. The resulting compound was reacted with 2.4 mmoles, O.δlg) of Z-Dap(Boc)-OH, 2.4 mmoles, 0.77g of TBTU and 7.51 mmoles, 1.31 mL of DIPEA in the presence of 35 mL of dry DMF. The reaction mixture was stirred at 0°C for 24 hr. The solvent was removed by rotary evaporation to yield an oil, which was dissolved in 25 mL of EtOAc and washed with H 2 0, 5% citric acid, sat. NaHCθ 3 , brine and dried over MgSθ 4 . This yielded the protected core chelator backbone B. The Boc group on B was removed by stirring with 5 mL of TFA and 5 mL of CH 2 C1 2 . The reaction mixture was stired for 2 hr and then the solvent removed under vacuum. Subsequently, 3 washes of CH 2 C1 was performed to remove traces of TFA. Coupling of the guanidino benzoic acid was achieved by mixing 0.8g, 1.25 mmoles of B with 0.285g, 1.32 mmoles of guanidino benzoic acid in the presence of 0.424g, 1.32 mmoles of TBTU, 740 mL, 4.25 mmoles of DIPEA in 15 L of DMF. The reaction mixture was stirred overnite at 0°C before work-up to yield the protected functionalized chelator as an oil. Removal of the protecting groups (OBzl and Z) was achieved by dissolving 60 mg of C in 1-2 mL of TFA. The reaction mixture was cooled to -16°C in a acetone/dry ice bath. TFMSA 1-2 mL was added dropwise while maintaining the temp. about -10°C C. 0.4 mL of anisole was added and the reaction mixture which turned purple was stirred at -10°C for an additional 3 hr. Subsequently 45 mL of cold diethyl ether was added to the reaction mixture and the temperature was lowered to about -35 C. The mixture was stirred under these conditions for 0.5 hr, upon which the temperature was further lowered to about -78°C and stirred for another 1.5 hr . The white precipitate formed was filtered through a medium fritted funnel and washed several times with cold ether. The precipitate was transferred to a 100 mL flask and dissolved in 20 mL of a water : acetone (1:1) mixture. This solution was treated with 1.5 mL of Bio-Rad- AG 1x2 (acetate) prewashed resin. The mixture was stirred for 30 minutes upon which the pH changed from 1.0 to 4.5. The soution was filtered, the resin washed (3 x 5 L) with water and the filtrate lyophilized. Purification of the crude product was achieved by preparative HPLC (Method used a Rainin instrument and a Vydac C18 column (5 cm x 25 cm) at a flow rate of 15 mL/min with a gradient mobile phase from 2% B to 20% B over 30 min (A = 100% water with 0.1% TFA and B = 50% aqueous acetonitrile with 0.1% TFA) monitored at 220 run. Ret. time (min): 16.9. The compound was analysed using the method indicated: analytical HPLC method used a Hewlett Packard model 1050 instrument and a Vydac C18 column (4.6 mm x 25 cm) at a flow rate of 1 mL/min with a gradient mobile phase from 2% B to 100% B over 45 min (A = 100% water with 0.1% TFA and B = 90% aqueous acetonitrile with 0.1% TFA) monitored at 220 run. Ret. time (min): 10.11. MS-FAB m/z calcd. for C 2 oH 25 N 7 θ 5 S+H: 476.53; Found: 476.3. Example 2 Preparation of 3-(3-((4- (amidinoamino) phenyl) carbonylamino)propanoylamino) -3- (N- (2- thienylmethyl ) carbamoyl ) propanoic acid Synthesis of Example 2 was achieved by a procedure similar to that used in Example 1, except that Boc-β-Ala instead of Z-Dap (Boc) -OH was used to prepare the chelator backbone . Purification of the crude product was achieved by preparative HPLC (Method used a Rainin instrument and a Vydac C18 column (5 cm x 25 cm) at a flow rate of 15 mL/min with a gradient mobile phase from 2% B to 20% B over 30 min (A = 100% water with 0.1% TFA and B = 50% aqueous acetonitrile with 0.1% TFA) monitored at 220 nm. Ret. time (min) : 20.1. The compound was analysed using the method indicated: analytical HPLC method used a Hewlett Packard model 1050 instrument and a Vydac C18 column (4.6 mm x 25 cm) at a flow rate of 1 mL/min with a gradient mobile phase from 2% B to 100% B over 45 min (A = 100% water with 0.1% TFA and B = 90% aqueous acetonitrile with 0.1% TFA) monitored at 220 nm. Ret. time (min): 10.3. MS-FAB m/z calcd. for C 2 oH 2 N 6 θ5S+H: 461.5; Found: 461.2. Example 3 Preparation of 3- ( (acetylamino)methylthio) -2- (2- (3- ( (4- ( ( amidinoamino ) methyl ) phenyl ) carbonylamino ) -2 - aminopropanoylamino) acetylamino)propanoic acid (Example 3a) 3- ( (acetylamino)methylthio) -2-(2-(3-((4- ( (amidinoamino) methyl) phenyl) carbonylamino) -2- aminopropanoylamino) -3 -carboxypropanoylamino)propanoic acid (Example 3b) 3- ( (acetylamino)methylthio) -2- (2- (3- ( (4- (amidinoamino) phenyl) carbonylamino) -2 -aminopropanoylamino) - 3-carboxypropanoylamino)propanoic acid (Example 3c) and 3- ( (acetylamino)methylthio) -2-(2-(3-((4- (amidinoamino) phenyl ) carbonylamino) propanoylamino) -3 - carboxypropanoylamino)propanoic acid (Example 3d) Synthesis of Examples 3a-d was achieved by manual solid phase peptide synthesis using fmoc-teabag chemistry on a wang resin solid support. The 5.0 x 5.0 cm teabags were made from 0.75 mm mesh polypropylene filters (Spectra Filters) and filled with 0.5 g of the commercially available S-acetamidomethyl-L-cysteine on Wang resin. In all cases synthesis of the protected tri-peptide resin intermediate was achieved using sequential coupling of the respective fmoc-amino acids and guanidinomethyl- or guanidinobenzoic acid to the S-acetamidomethyl-L-cysteine on Wang resin. Standard piperidine deprotection and HBTU/TBTU coupling methods were used for the coupling of the amino acids. Simultaneous cleavage from the resin and deprotection of the OtBu and Boc groups was achieved using a cocktail of TFA/triisopropylsi-lane/water in the ratio 95:2.5:2.5. Purification of the crude products was achieved by preparative HPLC (Method used a Rainin instrument and a Vydac C18 column (5 cm x 25 cm) at a flow rate of 15 mL/min with a gradient mobile phase from 20% B to 40% B over 40 min (A = 100% water with 0.1% TFA and B = 50% aqueous acetonitrile with 0.1% TFA) monitored at 220 run. Ret. Time (min): Example 3a: 16.97; Example 3b: 17.45; Example 3c: 12.81; Example 3d: 13.8. The compounds were then analysed using the method indicated: analytical HPLC method used a Hewlett Packard model 1050 instrument and a Vydac C18 column (4.6 mm x 25 cm) at a flow rate of 1 mL/min with a gradient mobile phase from 2% B to 100% B over 35 min (A = 100% water with 0.1% TFA and B = 90% aqueous acetonitrile with 0.1% TFA) monitored at 220 run. Ret. Time (min) : Example 3a: 8.55; Example 3b: 9.01; Example 3c: 8.33; Example 3d: 11.06. Example 3a: MS-FAB m/z calcd. for C 2 oH 30 N 8 0 6 S+H: 511.6; Found: 511.2. Example 3b: MS-FAB m/z calcd. for C 22 H 32 N 8 0 8 S+H: 569.6; Found: 569.2. Example 3c: MS-FAB m/z calcd. for C 2 ιH 30 N 8 O 8 S+H: 555.6; Found: 555.3. Example 3d: MS-FAB m/z calcd. for C 2 ιH 29 N 7 0 8 S+H: 540.6; Found: 540.2. Example 4 Preparation of the Tc-99m complex of Example 3c A solution of the Example 3c was prepared by dissolving 0.2 mg in 0.5 mL of 20 mM phosphate buffer (pH 11) . To this solution was added 0.2 mL of 99ιn Tcθ 4 ~ (30 mCi). To this was added a 0.2 mL of a sat. stannous tartarate solution and the reaction mixture heated at 80°C for 30 min followed by cooling at RT. After cooling about 2 minutes, 20 μL of the solution was analyzed by the HPLC method described below: The radiochemical purity (% RCP) of the resulting complex was determined using HPLC. The method used a Hewlett Packard 1050 instrument and a Vydac C18 column (4.6 mm x 25 cm) at a flow rate of 1 mL/min with a gradient mobile phase from 100% A (10 mM phosphate buffer, pH 6.0), to 7% B (acetonitrile) at 15 min and 80% B at 25 min. RCP values were obtained at 0.5, 3 and 6 hr post-heating of the kits (RCP > 90%, n=3 ) . Example 5 Preparation of the Tc-99m complex of Example 3c A solution of the Example 3c was prepared by dissolving 0.2 mg in 0.25 mL of 20 mM phosphate buffer (pH 11) . To this solution was added 1.0 mL of decayed Tc-99m generator eluate and 0.15 mL of a sat. stannous tartarate solution. The reaction mixture was heated at 80°C for 30 min followed by cooling at RT. After cooling about 2 minutes, 20 μL of the solution was analyzed by the HPLC method described in example 4. For comparison the Tc-99m complex as described in example 4 was also simultaneously prepared and analyzed by HPLC. The radio chromatograms of the Tc-99m and the Tc- 99 complexes had similar retention times indicating the formation of similar species at both the "tracer" and the macroscopic level. Three batches of the Tc-99m complex of Example 3c were evaluated in the GPIIb/IIIa binding assay using hPRP and found to have at least preferred IC 50 (μM) values . Utility The radiolabeled compounds of the present invention are useful as radiopharmaceuticals for imaging a thrombus such as may be present in a patient with unstable angina, myocardial infarction, transient ischemic attack, stroke, atherosclerosis, diabetes, thrombophlebitis, pulmonary emboli, or prosthetic cardiac devices such as heart valves, and thus may be used to diagnose such present or potential disorders. The patient may be any type of a mammal, but is preferably a human. The radiolabeled compounds may be used alone, or may be employed as a composition with a radiopharmaceutically acceptable carrier, and/or in combination with other diagnostic or therapeutic agents. Suitable radiopharmaceuticals carriers and suitable amounts thereof are well known in the art, and can be found in, for example, Remington's Pharmaceutical Sciences, Gennaro, A.R., ed. , Mack Publishing Company, Easton, PA (1985), and The United States Pharmacopia-The National Formulary, 22nd Revision, Mack Printing Company, Easton, PA (1990), standard reference texts in the pharmaceutical field. Other materials may be added, as convenient, to stabilize the composition, as those skilled in the art will recognize, including antioxidizing agents such as sodium bisulfite, sodium sulfite, ascorbic acid, gentisic acid or citric acid (or their salts) or sodium ethylenediamine tetraacetic acid (sodium EDTA) , as is well known in the art. Such other materials, as well as suitable amounts thereof, are also described in Remington's Pharmaceutical Sciences and The United States Pharmacopia-The National Formulary, cited above . The present invention also includes radiopharmaceutical kits containing the compounds of the present invention. Such kits may contain the compounds in sterile lyophilized form, and may include a sterile container of a radiopharmaceutically acceptable reconstitution liquid. Suitable reconstitution liquids are disclosed in Remington's Pharmaceutical Sciences and The United States Pharmacopia- The National Formulary, cited above. Such kits may alternatively contain a sterile container of a composition of the radiolabeled compounds of the invention. Such kits may also include, if desired, other conventional kit components, such as, for example, one or more carriers, or one or more additional vials for mixing. Instructions, either as inserts or labels, indicating quantities of the labeled compounds of the invention and carrier, guidelines for mixing these components, and protocols for administration may also be included in the kit. Sterilization of the containers and any materials included in the kit and lyophilization (also referred to as freeze- drying) of the labeled compounds of the invention may be carried out using conventional sterilization and lyophilization methodologies known to those skilled in the art . Another aspect of the present invention is diagnostic kits for the preparation of radiopharmaceuticals . Diagnostic kits of the present invention comprise one or more vials containing the sterile, non-pyrogenic, formulation comprised of a predetermined amount of a compound of formula (I) , a reducing agent, and optionally a solubilization aid or other components such as transfer ligands, buffers, lyophilization aids, stabilization aids, and bacteriostats . The inclusion of one or more optional components in the formulation will frequently improve the ease of synthesis of the radiopharmaceutical by the practising end user, the ease of manufacturing the kit, the shelf-life of the kit, or the stability and shelf-life of the radiopharmaceutical. The improvement achieved by the inclusion of an optional component in the formulation must be weighed against the added complexity of the formulation and added cost to manufacture the kit. The one or more vials that contain all or part of the formulation can independently be in the form of a sterile solution or a lyophilized solid. Solubilization aids useful in the preparation of radiopharmaceuticals and in diagnostic kits useful for the preparation of said radiopharmaceuticals include but are not limited to ethanol, glycerin, polyethylene glycol, propylene glycol, polyoxyethylene sorbitan monooleate, sorbitan monoloeate, polysorbates, poly (oxyethylene) poly (oxypropylene) oly (oxyethylene) block copolymers (Pluronics) and lecithin. Preferred solubilizing aids are polyethylene glycol, and Pluronics. Buffers useful in the preparation of radiopharmaceuticals and in diagnostic kits useful for the preparation of said radiopharmaceuticals include but are not limited to phosphate, citrate, sulfosalicylate, and acetate. A more complete list can be found in the United States Pharmacopeia . Lyophilization aids useful in the preparation of diagnostic kits useful for the preparation of radiopharmaceuticals include but are not limited to mannitol, lactose, sorbitol, dextran, Ficoll, and polyvinylpyrrolidine (PVP) . Stabilization aids useful in the preparation of radiopharmaceuticals and in diagnostic kits useful for the preparation of the same include but are not limited to ascorbic acid, cysteine, monothioglycerol, sodium bisulfite, sodium metabisulfite, gentisic acid, and inositol . Bacteriostats useful in the preparation of radiopharmaceuticals and in diagnostic kits useful for the preparation of said radiopharmaceuticals include but are not limited to benzyl alcohol, benzalkonium chloride, chlorbutanol, and methyl, propyl or butyl paraben. A component in a diagnostic kit can also serve more than one function. A reducing agent can also serve as a stabilization aid, a buffer can also serve as a transfer ligand, a lyophilization aid can also serve as a transfer, ancillary or co-ligand and so forth. The predetermined amounts of each component in the formulation are determined by a variety of considerations that are in some cases specific for that component and in other cases dependent on the amount of another component or the presence and amount of an optional component . In general, the minimal amount of each component is used that will give the desired effect of the formulation. The desired effect of the formulation is that the practising end user can synthesize the radiopharmaceutical and have a high degree of certainty that the radiopharmaceutical can be safely injected into a patient and will provide diagnostic information about the disease state of that patient. The diagnostic kits of the present invention may also contain written instructions for the practising end user to follow to synthesize the radiopharmaceuticals . These instructions may be affixed to one or more of the vials or to the container in which the vial or vials are packaged for shipping or may be a separate insert, termed the package insert. To carry out one of the methods of the present invention, the radiolabeled compounds are generally administered intravenously, by bolus injection, although they may be administered by any means that produces contact of the compounds with platelets. Suitable amounts for administration will be readily ascertainable to those skilled in the art, once armed with the present disclosure. The dosage administered will, of course, vary depending up such known factors as the particular compound administered, the age, health and weight or the nature and extent of any symptoms experienced by the patient, the amount of radiolabeling, the particular radionuclide used as the label, the rate of clearance of the radiolabeled compounds from the blood. Acceptable ranges for administration of radiolabeled materials are tabulated, for example, in the Physicians Desk Reference (PDR) for Nuclear Medicine, published by Medical Exonomics Company, a well-known reference text. A discussion of some of the aforementioned considerations is provided in Eckelman et al . , J. Nucl. Med. , Vol. 209, pp. 350-357 (1979) . By way of general guidance, a dosage range of the radiolabeled compounds of the invention may be between about 1 and about 40 mCi . Once the radiolabeled compounds of the invention are administered, the presence of thrombi may be visualized using a standard radioscintographic imaging system, such as, for example, a gamma camera or a computed tomographic device. Such imaging systems are well known in the art, and are discussed, for example, in Macovski, A., Medical Imaging Systems, Information and Systems Science Series, Kailath, T., ed., Prentice-Hall, Inc., Englewood Cliffs, NJ (1983). Particularly preferred are single-photon emission computed tomography (SPECT) and positron emission tomography (PET) . Specifically, imaging is carried out by scanning the entire patient, or a particular region of the patient suspected of having a thrombus formation, using the radioscintographic system, and detecting the radioisotope signal. The detected signal is then converted into an image of the thrombus by the system. The resultant images should be read by an experienced observer, such as, for example, a nuclear medicine physician. The foregoing process is referred to herein as "imaging" the patient. Generally, imaging is carried out about 1 minute to about 48 hours following administration of the radiolabeled compound of the invention. The precise timing of the imaging will be dependant upon such factors as the half-life of the radioisotope employed, and the clearance rate of the compound administered, as will be readily apparent to those skilled in the art. Preferably, imaging is carried out between about 1 minute and about 4 hours following administration . The advantage of employing the radiolabeled compounds of the invention, which have the ability to localize specifically and with high affinity in thrombi, to detect the presence of thrombi and/or to diagnose thromboembolic disorders in a patient, will be readily apparent to those skilled in the art, once armed with the present disclosure. Platelet-Fibrinoqen Binding Assay Binding of 125ι_fibrinogen to platelets was performed as described by Bennett et al . (1983) Proc . Natl. Acad. Sci. USA 80: 2417-2422, with some modifications as described below. Human PRP (h-PRP) was applied to a Sepharose column for the purification of platelet fractions. Aliquots of platelets (5 X 10^ cells) along with 1 mM calcium chloride were added to removable 96 well plates prior to the activation of the human gel purified platelets (h-GPP) . Activation of the human gel purified platelets was achieved using ADP, collagen, arachidonate, epinephrine, and/or thrombin in the presence of the ligand, 125 _fibrinogen. The 12 5 _fibrinogen bound to the activated, platelets was separated from the free form by centrifugation and then counted on a gamma counter. For an IC50 evaluation, the test compounds were added at various concentrations prior to the activation of the platelets . Preferred compounds of the present invention would include those compounds having an IC 50 value of less than about 1 mM, more preferably an IC 50 value of less than about 0.1 mM, even more preferably an IC 50 value of less than about 0.01 mM, still more preferably an IC 50 value of less than about 0.001 mM, and most preferably an IC 50 value of about 0.0005 mM. The disclosures of each patent and publication cited in this document are hereby incorporated herein by reference, in their entirety. Obviously, numerous modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that within the scope of the appended claims, the invention may be practiced otherwise that as specifically described herein.

Claims: WHAT IS CLAIMED AS NEW AND DESIRED TO BE SECURED BY LETTER PATENT OF UNITED STATES IS; 1. A compound of formula (I) : or a pharmaceutically acceptable salt form thereof, wherein: R 1 is selected from the group H and NH ; R 2 is selected from the group CH 2 C0 H and CH 2 CH C0 2 H; R 3 is selected from the group: wherein * indicates where R 3 is attached to formula I; R 4 is selected from the group CH 2 NHC (=NH)NH 2 , NHC(=NH)NH 2 , C(=NH)NH 2 , CH 2 C(=NH)NH 2 , and CH 2 CH 2 C (=NH)NH 2 ; and n is 0 or 1. 2. A compound according to Claim 1, wherein; R 4 is NHC(=NH)NH 2 . 3. A compound according to Claim 2, wherein; R 1 is NH 2 ; R 2 is CH 2 C0 2 H; wherein * indicates where R 3 is attached to formula I; and, n is 0. 4. A compound according to Claim 2, wherein; R 1 is H; R 2 is CH 2 C0 2 H; wherein * indicates where R 3 is attached to formula I; and, n is 0. 5. A compound according to Claim 2, wherein; R 1 is NH 2 ; R 2 is CH 2 C0 2 H; R3 IS wherein * indicates where R 3 is attached to formula I; and, n is 1. 6. A compound according to Claim 2, wherein; R 1 is NH 2 ; R 2 is CH 2 C0 2 H; wherein * indicates where R 3 is attached to formula I; and, n is 0. 7. A compound according to Claim 2, wherein; R 1 is H; R 2 is CH 2 C0 2 H; wherein * indicates where R 3 is attached to formula I; and, n is 0. 8. A kit for preparing a radiopharmaceutical comprising a predetermined quantity of a compound according to Claim 1 or a pharmaceutically acceptable salt form thereof . 9. A radiopharmaceutical comprising a complex of a compound according to Claim 1 and 99m Tc _ 10. A radiopharmaceutical composition comprising a radiopharmaceutically acceptable carrier and a 99m r p c labeled compound according to Claim 1. 11. A method of imaging, comprising: (i) administering to said mammal an effective amount of a 99 m Tc labeled compound according to Claim 1, and (ii) imaging the mammal. 12. The method according to Claim 11, wherein the method is a method of visualizing sites of platelet deposition in a mammal. 13. The method according to Claim 11, wherein the method is a method of determining platelet deposition in a mammal . 14. The method according to Claim 11, wherein the method is a method of diagnosing a disorder associated with platelet deposition in a mammal. 15. A sterile, non-pyrogenic kit for radioimaging a mammal, comprising: (a) a predetermined quantity of a compound according to Claim 1; and, (b) a predetermined quantity of a reducing agent. 16. A kit according to Claim 15, wherein components (a) and (b) are contained in a vial. 17. A kit according to Claim 15, wherein component (a) is contained in a first vial and component (b) is contained in a second vial. 18. A kit according to Claim 15, wherein the reducing agent is stannous chloride.

Inventors: RAJOPADHYE MILIND, SINGH PRAHLAND R, RAJOPADHYE, MILIND, SINGH, PRAHLAND, R.
Applicants: DU PONT PHARM CO, RAJOPADHYE MILIND, SINGH PRAHLAND R, DU PONT PHARMACEUTICALS COMPANY, RAJOPADHYE, MILIND, SINGH, PRAHLAND, R.
Application year: 1999
Main classification: C07K5
IPC codes: A61K51, C07K5, G01N33