GASTRIN RECEPTOR-AVID PEPTIDE CONJUGATES

Abstract: A compound for use as a therapeutic or diagnostic radiopharmaceutical includes a group capable of complexing a medically useful metal attached to a moiety which is capable of binding to a gastrin releasing peptide receptor. A method for treating a subject having a neoplastic disease includes administering to the subject an effective amount of a radiopharmaceutical having a metal chelated with a chelating group attached to a moiety capable of binding to a gastrin releasing peptide receptor expressed on tumor cells with subsequent internalization inside of the cell. A method of forming a therapeutic or diagnostic compound includes reacting a metal synthon with a chelating group covalently linked with a moiety capable of binding a gastrin releasing peptide receptor.

Description: GASTRIN RECEPTOR-AVID PEPTIDE CONJUGATES TECHNICAL FIELD This invention relates to radionuclide-labeled compounds useful as radiopharmaceuticals. More particularly, the present invention relates to conjugates of bombesin (BBN) analogues and a metal complexing group which, when complexed to a radionuclide, are useful therapeutic and imaging agents for cancer cells that express gastrin releasing peptide (GRP) receptors. BACKGROUND OF THE INVENTION Detection and treatment of cancers using radiopharmaceuticals that selectively target cancers in human patients has been employed for several decades. Unfortunately, only a limited number of site-directed radiopharmaceuticals that exhibit highly specific in vivo localization in or near cancer cells are currently in routine use, as being approved by the United States Food and Drug Administration (FDA). There is a great deal of interest in developing new radioactive drugs due to the emergence of more sophisticated biomolecular carriers that have high affinity and high specificity for in vivo targeting of tumors. Several types of agents are being developed and have been investigated including monoclonal antibodies (MAbs), antibody fragments (F^'s and (F AB ) 2 's), receptor-avid peptides [Bushbaum, 1995; Fischman et al., 1993; Schubiger et al. 1996]. The potential utility of using radiolabeled receptor-avid peptides for producing radiopharmaceuticals is best exemplified by nι In- DTPA-conjugated octreotide (an FDA approved diagnostic imaging agent, Octreoscan®, marketed in the United States, by Mallinckrodt Medical, Inc.) [Lowbertz et al. 1994]. This radiopharmaceutical is an ul In-DTPA conjugate of Octreotide, a small peptide analogue of the human hormone somatostatin. This drug specifically binds to somatostatin receptors that are over-expressed on neuroendocrine cancers (e.g., carcinoid Ca, neuroblastoma, etc.) as well as others [Krenning et al., 1994], Since indium- 111 ( U1 ln) is not the ideal radionuclide for scintigraphic imaging, other somatostatin analogues and other receptor- avid biomolecules that are labeled with 99m Tc (the optimal radionuclide for diagnostic imaging) are being studied and developed [Eckelman, 1995; Vallabhajosula et al., 1996]. Bombesin (BBN) is a 14 amino acid peptide that is an analogue of human gastrin releasing peptide (GRP) that binds to GRP receptors with high specificity and has an affinity similar to GRP [Davis et al., 1992]. GRP receptors have been shown to be over-expressed or uniquely expressed on several types of cancer cells. Binding of GRP receptor agonists (also autocrine factors) increases the rate of cell division of these cancer cells. For this reason, a great deal of work has been, and is being pursued to develop BBN or GRP analogues that are antagonists [Davis et al., 1992; Hoffken, 1994; Moody et al., 1996; Coy et al., 1988; Cai et al., 1994]. These antagonists are designed to competitively inhibit endogenous GRP binding to GRP receptors and reduce the rate of cancer cell proliferation [Hoffken, 1994]. Treatment of cancers using these antagonists with these non-radioactive peptides requires chronic injection regimens (e.g., daily, using large quantities of the drug). In designing an effective receptor-avid radiopharmaceutical for use as a diagnostic or therapeutic agent for cancer, it is important that the drug have appropriate in vivo targeting and pharmacokinetic properties [Fritzberg et al., 1992; Eckelman et al., 1993]. For example, it is essential that the radiolabeled receptor-avid peptide have high specific uptake by the cancer cells (e.g., via GRP receptors). In addition, it is necessary that once the radionuclide localizes at a tumor site, it must remain there for an extended time to deliver a highly localized radiation dose to the tumor. In order to achieve sufficiently high specific uptake of radiolabeled BBN analogues in tumors, the binding affinity of promising derivatives must be high (i.e., K d = 1-5 nmolar or less) with prolonged retention of radioactivity [Eckelman et al., 1995; Eckelman, et al., 1993]. Work with 125 I-BBN derivatives has shown, however, that for cancer cells that bind the 125 I-BBN derivatives (whether they be agonists or antagonists), the radioactivity is either washed off or expelled from the cells (in vitro) at a rapid rate [Hoffman et al., 1997]. Thus, these types of derivatives have a low probability of remaining "trapped" at the tumor site (in vivo) sufficiently long to be effective therapeutic or diagnostic agents. Developing radiolabeled peptides that are cleared efficiently from normal tissues is also an important and especially critical factor for therapeutic agents. When labeling biomolecules (e.g., MAb, F AD 'S or peptides) with metallic radionuclides (via a chelate conjugation), a large percentage of the metallic radionuclide (in some chemical form) usually becomes "trapped" in either the kidney or liver parenchyma (i.e., is not excreted into the urine or bile) [Duncan et al., 1997; Mattes, 1995]. For the smaller radiolabeled biomolecules (i.e., peptides or F^'s), the major route of clearance of activity is through the kidneys which in turn retain high levels of the radioactive metal (i.e., normally > 10-15% of the injected dose) [Duncan et al., 1997]. This presents a major problem that must be overcome in the development of therapeutic agents that incorporate metallic radionuclides, otherwise the radiation dose to the kidneys would be excessive. For example, lu In-octreotide, the FDA approved diagnostic agent, exhibits high uptake and retention in kidneys of patients [Eckelman et al., 1995]. Even though the radiation dose to the kidneys is higher than desirable, it is tolerable in that it is a diagnostic radiopharmaceutical (it does not emit alpha- or beta-particles), and the renal dose does not produce observable radiation induced damage to the organ. It has now been found that conjugating BBN derivatives which are agonists in non-metallated conjugates whichthat exhibit binding affinities to GRP receptors that are either similar to or approximately an order of magnitude lower than the parent BBN derivative. [Li et al., 1996a] These data coupled with our recent results show that it is now possible to add radiometal chelates to BBN analogues, which are agonists, and retain GRP receptor binding affinities that are sufficiently high (i.e., approx. 1-5 nmolar K d 's) for further development as potential radiopharmaceuticals. These agonist conjugates are transported intracellularly after binding to cell surface GRP receptors and retained inside of the cells for extended time periods. In addition, in vivo studies in normal mice have shown that retention of the radioactive metal in the kidneys was low (i.e., <5%) with the majority of the radioactivity excreted into the urine. According to one aspect of the present invention, there is provided a BBN conjugate consisting of essentially a radio-metal chelate covalently appended to the receptor binding region of BBN [e.g., BBN(8- 14)] to form radiolabeled BBN analogues that have high specific binding affinities with GRP receptors. These analogues are retained for long times inside of GRP expressing cancer cells. Furthermore, their clearance from the bloodstream, into the urine with minimal kidney retention, is efficient. Preferably, the radiometals are selected from 99m Tc, 186 188 Re, 105 Rh, 153 Sm, 166 Ho, 90 Y or 199 Au, all of which hold the potential for diagnostic (i.e., 99m Tc) or therapeutic (i.e., 186 188 R e , 105 Rh, 153 Sm, 166 Ho, 90 Y, and 199 Au) utility in cancer patients [Schubiger et al, 1996; Eckelman, 1995; Troutner, 1978]. SUMMARY OF THE INVENTION In accordance with the present invention, there is provided a compound for use as a therapeutic or diagnostic radiopharmaceutical which includes a group which is capable of complexing a metal attached to a moiety capable of binding to a gastrin releasing peptide receptor. Additionally, in accordance with the present invention, a method for treating a subject having a neoplastic disease which includes the step of administering to the subject an effective amount of a radiopharmaceutical having a metal chelated with a chelating group attached to a moiety capable of binding to a gastrin releasing peptide receptor on a cancer cell, subsequently intracellularly transported and residualized inside the cell, is disclosed. Additionally, in accordance with the present invention, a method of forming a therapeutic or diagnostic compound including the step of reacting a metal synthon with a chelating group covalently linked with a moiety capable of binding a gastrin releasing peptide receptor is disclosed. BRIEF DESCRIPTION OF THE DRAWINGS Other advantages of the present invention will be readily appreciated as the same becomes better understood by reference to the following detailed description when considered in connection with the accompanying drawings wherein: FIGURE 1 illustrates a radiometal conjugate according to the present invention; FIGURE 2 is an ORTEP drawing of the {Rh[16]aneS 4 -olCl 2 } + , illustrating the crystal structure a Rhodium macrocycle; FIGURE 3 illustrates a coupling reaction wherein a spacer group is coupled to a bombesin agonist binding moiety; FIGURE 4 illustrates a coupling reaction for coupling a metal chelate to a peptide; FIGURE 5 illustrates several iodinated bombesin analogues including their IC 50 's; FIGURE 6 illustrates several tethered bombesin analogues; FIGURE 7 illustrates several [16]aneS 4 bombesin analogues; FIGURE 8 is a graph illustrating IC 50 analysis wherein %-I-125-BBN total uptake versus molar concentration of displacing ligand is shown; FIGURE 9 illustrates several Rhodium-[16]aneS 4 bombesin analogues; FIGURE 10 illustrates an HPLC chromatogram of Rhodium-BBN-37 wherein (A) illustrates 105 RhCl 2 -BBN-37 and (B) illustrates RhCl 2 -BBN-37; FIGURE 11 is a graph illustrating 125 I-Tyr -bombesin internalization efflux from Swiss 3T3 cells; FIGURE 12 illustrates 1-125 bombesin internalization efflux in 1-125 free buffer wherein 12 T-Tyr 4 -BBN vs. 125 I-Lys 3 -BBN efflux from Swiss 3T3 cells is shown; FIGURE 13 is a graph illustrating the efflux of 105 Rh-BBN- 37 from Swiss 3T3 cells; FIGURE 14 illustrates several 105 Rhodium bombesin analogues including their IC 50 's; FIGURE 15 is a graph illustrating 105 Rh-BBN-61 efflux from Swiss 3T3 cells; FIGURE 16 is a graph illustrating the efflux of 105 Rh-BBN- 22 vs. 105 Rh-BBN-37 from Swiss 3T3 cells; FIGURE 17 are graphs illustrating Pancreatic CA cell binding wherein (A) illustrates the efflux 125 I-Tyr 4 -BBN from CF PACl cells and (B) illustrates the efflux of 105 Rh-BBN-37 from CF PACl cells; and FIGURE 18 are graphs illustrating Prostate CA cell binding wherein (A) illustrates the efflux of 125 I-Tyr 4 -BBN from PC-3 cells and (B) illustrates the efflux of 105 Rh-BBN-37 from PC-3 cells. FIGURE 19 illustrates 5 [16]aneS 4 bombesin analogues. FIGURE 20 illustrates 4 Rhodium-[ 16]aneS 4 bombesin analogues. FIGURE 21 illustrates 3 different N 3 S-BFC A conjugates of BBN(7-14). FIGURE 22 illustrates on HPLC chromatogram of 99m Tc- BBN-122. FIGURE 23 is a graph illustrating 99m TC-BBN-122 internalization efflux from human prostate cancer cells (PC-3 cells). FIGURE 24 is a graph illustrating 99m Tc-BBN-122 internalization efflux from human pancreatic tumor cells (CFPAC-1 cells). FIGURE 25 is a graph illustrating 99m Tc-RP-414-BBN-42 retention in PC-3 prostate cancer cells. FIGURE 26 is a graph illustrating 99mTc-42 retention in CFPAC-1 pancreatic cancer cells. DETAILED DESCRIPTION OF THE INVENTION According to the present invention, compounds for use as diagnostic and/or therapeutic radiopharmaceuticals include a group capable of complexing a metal attached to a moiety capable of binding to a gastrin releasing peptide (GRP) receptor as shown in Figure 1. The moiety capable of specific binding to the GRP receptor is a GRP agonist. A GRP agonist would activate or produce response by the GRP receptor upon interaction with the GRP receptor and would be subsequently internalized inside of the cell by endocytosis. In contrast, a GRP antagonist would counteract the effect of an agonist and would not be internalized inside of the cell. More specifically, the GRP agonist is a compound such as selected amino acid sequences or peptidomimetics which are known to activate the cell following binding with high affinity and selectivity to GRP receptors and that can be covalently linked to the metal complexing group. Many examples of specific modifications of the BBN(8- 14) that can be made to produce sequences with high antagonistic and agonistic binding affinity for GRP repectors have been reported by numerous investigations [Davis et al., 1992; Hoffken, 1994; Moody et al., 1996; Coy et al, 1988; Cai et al., 1994; Moody et al, 1995; Leban et al., 1994; Cai et al., 1992]. In a preferred embodiment of the present invention, the metal complexing group or moiety is a chelating agent or chelator which complexes to metals such as 105 Rh-, 186/]88 R e -, 99m Tc, 153 Sm, 166 Ho, 90 Y or 199 Au. The chelating agent or chelator is attached or bound to the GRP agonist "binding region" to produce a conjugate that retains its capability for high affinity and specific binding to GRP receptors. In a more preferred embodiment of the present invention, the GRP agonist is a bombesin (BBN) analogue and/or a derivative thereof. The BBN derivative or analog thereof preferably contains either the same primary structure of the BBN binding region [i.e., BBN(8-14)] or similar primary structures, with specific amino acid substitutions, that will specifically bind to GRP receptors with better or similar binding affinities as BBN alone (i.e., K d = 1-5 nmolar) Compounds containing this BBN binding region (or binding moiety), when covalently linked to other groups (e.g., a radiometal chelate), are also referred to as BBN conjugates. In general, the compounds of the present invention have a structure of the general formula: X-Y-B wherein X is a group capable of complexing a metal, such as a radiometal; Y is a covalent bond on a spacer group; and B is a bombesin agonist binding moiety. The metal bound to the metal complexing group can be any suitable metal chosen for a specific therapeutic or diagnostic use including transition metals and γ and β emitting isotopes. Preferably, the metal is a radiometal such as 105 Rh-, 99m Tc-, 186/188 R e , 153 Sm-, 166 Ho-, 90 Y-, and 199 Au- whose chelates can be covalently linked (i.e., conjugated) to the specific BBN binding region via the N-terminal end of the primary binding sequence (e.g., BBN-8 or Trp 8 ) as shown in Figure 1. In a preferred embodiment, the radiometal complexes are positioned by being spaced apart from or remotely from the amino acid Trp 8 by the spacer groups. The spacer groups can include a peptide (i.e., > 1 amino acid in length), a hydrocarbon spacer of C,-C 10 or a combination of thereof. Preferably, the hydrocarbon spacer has is a C 3 -C 9 group. The resulting radio-labeled BBN conjugates retain high binding affinity and specificity for GRP receptors and are subsequently internalized inside of the cell. The BBN conjugates can further incorporate a spacer group or component to couple the binding moiety to the metal chelator (or metal binding backbone) while not adversely affecting either the targeting function of the BBN-binding moiety or the metal complexing function of the metal chelating agent. The term "spacer group" or "linker" refers to a chemical group that serves to couple the BBN binding moiety to the metal chelator while not adversely affecting either the targeting function of the BBN binding moiety or the metal complexing function of the metal chelator. Suitable spacer groups include peptides (i.e., amino acids linked together) alone, a non-peptide group (e.g., hydrocarbon chain) or a combination of an amino acid sequence and a non-peptide spacer. The type of spacer group used in most of the experimental studies described below in the Examples section were composed of a combination of L-glutamine and hydrocarbon spacers. A pure peptide spacer could consist of a series of amino acids (e.g., diglycine, triglycine, gly-gly-glu, etc.), in which the total number of atoms between the N-terminal residue of the BBN binding moiety and the metal chelator in the polymeric chain is < 12 atoms. The spacer can also include a hydrocarbon chain [i.e., R,- (CH 2 ) n -R 2 ] wherein n is 0-10, preferably n = 3 to 9, R, is a group (e.g., H 2 N-, HS-, -COOH) that can be used as a site for covalently linking the ligand backbone or the preformed metal chelator or metal complexing backbone; and R 2 is a group that is used for covalent coupling to the N- terminal NH 2 -group of the BBN binding moiety (e.g., R 2 is an activated COOH group). Several chemical methods for conjugating ligands (i.e., chelators) or preferred metal chelates to biomolecules have been well described in the literature [Wilbur, 1992; Parker, 1990; Hermanson, 1996; Frizberg et al., 1995]. One or more of these methods could be used to link either the uncomplexed ligand (chelator) or the radiometal chelate to the spacer group or to link the spacer group to the BBN(8-14) derivatives. These methods include the formation of acid anhydrides, aldehydes, arylisothiocyanates, activated esters, or N-hydroxysuccinimides [Wilbur, 1992; Parker, 1990; Hermanson, 1996; Frizberg et al., 1995]. The term "metal complexing chelator" refers to a molecule that forms a complex with a metal atom that is stable under physiological conditions. That is, the metal will remain complexed to the chelator backbone in vivo. More particularly, a metal complexing chelator is a molecule that complexes to a radionuclide metal to form a metal complex that is stable under physiological conditions and which also has at least one reactive functional group for conjugation with the BBN agonist binding moiety. Metal complexing chelators can include monodentate and polydentate chelators [Parker, 1990; Frizberg et al., 1995; Lister- James et al., 1997; Li et al, 1996b; Albert et al., 1991; Pollak et al., 1996; de Jong et al., 1997; Smith et al., 1997]. Metal complexing chelators include tetradentate metal chelators which can be macrocyclic and have a combination of four nitrogen and/or sulphur metal-coordinating atoms [Parker et al., 1990; Li et al., 1996b] and are designated as N 4 , S 4 , N 3 S, N 2 S 2 , NS 3 , etc. as shown in Figure 2. A number of suitable multidentate chelators that have been used to conjugate proteins and receptor-avid molecules have been reported [Frizberg et al., 1995; Lister- James et al., 1997; Li et al., 1996b; Albert et al., 1991; Pollak et al., 1996; de Jong et al., 1997]. These multidentate chelators can also incorporate other metal- coordinating atoms such as oxygen and phosphorous in various combinations. The metal binding complexing moiety can also include "3+1" chelators [Seifert et al.,1998]. For diagnostic purposes, metal complexing chelators preferably include chelator backbones for complexing the radionuclide metal 99m Tc. For therapeutic purposes, metal complexing chelators preferably include chelator backbones that complex the radionuclide metals 105 Rh, 186 188 R e , 153 Sm, 90 Y, 166 Ho, and 199 Au [Schubiger et al.,1996; Hoffken, 1994]. As was briefly described above, the term "bombesin agonist" or "BBN agonist" refers to compounds that bind with high specificity and affinity to GRP receptors, and upon binding to the GRP receptor, are intracellularly internalized. Suitable compounds include peptides, peptidomimetics and analogues and derivatives thereof. In particular, previous work has demonstrated that the region on the BBN peptide structure required for binding to GRP receptors spans from residue 8 through 14 [Davis et al., 1992; Hoffken, 1994; Moody et al., 1996; Coy, 1988; Cai et al., 1994]. The presence of methionine (Met) at position BBN- 14 will generally confer agonistic properties while the absence of this residue at BBN- 14 generally confers antagonistic properties [Hoffken, 1994]. It is well documented in the art that there are a few and selective number of specific amino acid substitutions in the BBN (8-14) binding region (e.g., D-Ala 11 for L-Gly 11 or D-Trp 8 for L-Trp 8 ), which can be made without decreasing binding affinity [Leban et al., 1994; Qin et al., 1994; Jensen et al., 1993]. In addition, attachment of some amino acid chains or other groups to the N-terminal amine group at position BBN-8 (i.e., the Trp 8 residue) can dramatically decrease the binding affinity of BBN analogues to GRP receptors [Davis et al, 1992; Hoffken, 1994; Moody et al., 1996; Coy, et al., 1988; Cai et al., 1994]. In a few cases, it is possible to append additional amino acids or chemical moieties without decreasing binding affinity. The effects of conjugating various side chains to BBN-8 on binding affinity, therefore, is not predicable. The BBN conjugates of the present invention can be prepared by various methods depending upon the selected chelator. The peptide portion of the conjugate can be most conveniently prepared by techniques generally established and known in the art of peptide synthesis, such as the solid-phase peptide synthesis (SPPS) approach. Solid-phase peptide synthesis (SPPS) involves the stepwise addition of amino acid residues to a growing peptide chain that is linked to an insoluble support or matrix, such as polystyrene. The C-terminal residue of the peptide is first anchored to a commercially available support with its amino group protected with an N-protecting agent such as a t-butyloxycarbonyl group (tBoc) or a fluorenylmethoxycarbonyl (FMOC) group. The amino protecting group is removed with suitable deprotecting agents such as TFA in the case of tBOC or piperidine for FMOC and the next amino acid residue (in N-protected form) is added with a coupling agent such as dicyclocarbodiimide (DCC). Upon formation of a peptide bond, the reagents are washed from the support. After addition of the final residue, the peptide is cleaved from the support with a suitable reagent such as trifluoroacetic acid (TFA) or hydrogen fluoride (HF). The spacer groups and chelator components are then coupled to form a conjugate by reacting the free amino group of the Trp 8 residue of the BBN binding moiety with an appropriate functional group of the chelator, metal chelator or spacer group, such as a carboxyl group or activated ester. The BBN conjugate can also incorporate a metal complexing chelator backbone that is peptidic and compatible with solid- phase peptide synthesis. In this case, the chelator backbone can be added to the BBN binding moiety in the same manner as described above or, more conveniently, the metal complexing chelator backbone coupled to the BBN binding moeity can be synthesized in toto starting from the C- terminal residue of the peptide and ending with the N-terminal residue of the metal complexing chelator structure. The chelator backbones used in accordance with the present invention are commercially available or they could be made by methods similar to those outlined in the literature [Frizberg et al., 1995; Lister- James et al, 1997; Li et al., 1996b; Albert et al., 1991; Pollak et al., 1996; de Jong et al., 1997; Smith et al., 1997; Seifert et al., 1998]. Attachment of the spacer groups to functionalizable atoms appended to the ligand backbone can be performed by standard methods known to those skilled in the art. For example, the HOBt/HBTU activated -COOH group on 5 -amino valeric acid (5-AVA) was reacted with the N-terminal amine on Gin 7 to produce an amide linkage as shown in Figure 3. Similarly, the -COOH group attached to the characterized [16]aneS 4 ligand was conjugated to the amine group on the hydrocarbon spacer (shown below) by reaction of the HOBt/HBTU activated carboxyl group appended to the [16]aneS 4 macrocycle with the terminal amine group on 5-AVA to form BBN-37 as shown in Figure 4. Other standard conjugation reactors that produce covalent linkages with amine groups can also be used [Wilbur, 1992; Parker, 1990]. The chelating framework, conjugated via Trp 8 , complexes the radiometals should form a 1 : 1 chelator to metal ratio. Since 99m Tc has a short half-life (6 hour) and is a diagnostic radionuclide, the method of forming the 99m Tc-BBN analogues should permit complexation (either directly or by transmetallation) of 99m Tc to the conjugated chelating framework in a one-step, high yield reaction (exemplified below in the Experimental Section). In contrast, the longer half lives of the therapeutic radionuclides (e.g., 105 Rh, 186188 R e , 153 Sm, 166 Ho, 90 Y, or 199 Au) permit formation of the corresponding radiolabeled BBN analogues by either a one step high yield complexation step or by preforming a 105 Rh-, I86 188 R e -, 153 Sm, 166 Ho, 90 Y or 199 Au chelate synthon followed by conjugation of the preformed complex to the N-terminal end of the BBN binding moiety. In all cases, the resulting specific activity of the final radiolabeled BBN derivative must be high (i.e., > ICi/μmole). Re- and Tc-conjugates Re and Tc are both in row VIIB of the Periodic Table and they are chemical congeners. Thus, for the most part, the complexation chemistry of these two metals with ligand frameworks that exhibit high in vitro and in vivo stabilities are the same [Eckelman, 1995]. Many 99m Tc or I86 188 R e complexes, which are employed to form stable radiometal complexes with peptides and proteins, chelate these metals in their +5 oxidation state [Lister- James et al., 1997]. This oxidation state makes it possible to selectively place 99m Tc- or 186 188 Re into ligand frameworks already conjugated to the biomolecule, constructed from a variety of 99m Tc(V) and/or 186/188 Re(V) weak chelates (e.g., 99m Tc- glucoheptonate, citrate, gluconate, etc.) [Eckelman, 1995; Lister- James et al., 1997; Pollak et al., 1996]. Tetradentate ligand frameworks have been shown to form well-defined, single chemical species in high specific activities when at least one thiol group or at least one hydroxymethylene phosphine group is present on the ligand backbone [Smith et al., 1997]. Ligands which form stable Tc(V) or Re(V) tetradentate complexes containing, but not limited to, amino N-atoms, amido-N- atoms, carboxy-O-atoms and thioether-S-atoms, are donor atoms that can also be present [Eckelman, 1995; Fritzberg et al., 1992; Parker, 1990; Frizberg et al., 1995; Pollak et al., 1996; Seifert et al., 1998]. Depending upon the mix of donor atoms (groups), the overall complex charge normally ranges from -1 to +1. Incorporation of the metal within the conjugate can be achieved by various methods commonly known in the art of coordination chemistry. When the metal is technetium-99m, the following general procedure can be used to form a technetium complex. A peptide-chelator conjugate solution is formed by initially dissolving the conjugate in aqueous alcohol such as ethanol. The solution is then degassed to remove oxygen. When an -SH group is present in the peptide, the thiol protecting group are removed with a suitable reagent, for example with sodium hydroxide, and are then neutralized with an organic acid such as acetic acid (pH 6.0-6.5). In the labeling step, sodium pertechnetate obtained from a molybdenum generator is added to a solution of the conjugate with a sufficient amount of a reducing agent, such as stannous chloride, to reduce technetium and is then heated. The labeled conjugate can be separated from the contaminants 99m TcO 4 " and colloidal 99m TcO 2 chromatographically, for example with a C-l 8 Sep Pak cartridge [Millipore Corporation, Waters Chromatography Division, 34 Maple Street, Milford, Massachusetts 01757]. In an alternative method, the labeling can be accomplished by a transchelation reaction. The technetium source is a solution of technetium complexed with labile ligands facilitating ligand exchange with the selected chelator. Examples of suitable ligands for transchelation includes tartrate, citrate, gluconate, and heptagluconate. It will be appreciated that the conjugate can be labeled using the techniques described above, or alternatively, the chelator itself may be labeled and subsequently coupled to the peptide to form the conjugate; a process referred to as the "prelabeled chelate" method. When labeled with diagnostically and/or therapeutically useful metals, peptide-chelator conjugates or pharmaceutically acceptable salts, esters, amides, and prodrugs of the present invention can be used to treat and/or detect cancers, including tumors, by procedures established in the art of radiodiagnostics and radiotherapeutics. [Bushbaum, 1995; Fischman et al, 1993; Schubiger et al., 1996; Lowbertz et al., 1994; Krenning et al., 1994]. A conjugate labeled with a radionuclide metal, such as technetium-99m, can be administered to a mammal, including human patients or subjects, by intravenous or intraperitoneal injection in a pharmaceutically acceptable carrier and/or solution such as salt solutions like isotonic saline. The amount of labeled conjugate appropriate for administration is dependent upon the distribution profile of the chosen conjugate in the sense that a rapidly cleared conjugate may be administered in higher doses than one that clears less rapidly. Unit doses acceptable for Tc-99m imaging radiopharmaceuticals inflammation are in the range of about 5-40 mCi for a 70kg individual. In vivo distribution and localization can be tracked by standard scintigraphic techniques at an appropriate time subsequent to administration; typically between thirty minutes and 180 minutes depending upon the rate of accumulation at the target site with respect to the rate of clearance at non-target tissue. The compounds of the present invention can be administered to a patient alone or as part of a composition that contains other components such as excipients, diluents, and carriers, all of which are well-known in the art. The compounds can be administered to patients either intravenously or intraperitoneally. There are numerous advantages associated with the present invention. The compounds made in accordance with the present invention forms a stable, well-defined 99m Tc or 186 188 R e conjugate analogues of BBN agonists. Similar BBN against analogues can also be made by using appropriate chelator frameworks for the respective radiometals, to form stable-well-defined products labeled with ,53 Sm, 90 Y, 166 Ho, ,05 Rh or 199 Au. The radiolabeled BBN agonist conjugates selectively bind to neoplastic cells expressing GRP receptors become internalized and are retained in the tumor cells for extended time periods. Incorporating the spacer group between the metal chelator and the BBN agonist binding moiety maximizes the uptake and retention of the radioactive metal inside of the neoplasts or cancer cells. The radioactive material that does not reach (i.e., does not bind) the cancer cells is preferentially excreted efficiently into the urine with minimal radiometal retention in the kidneys. The following examples are presented to illustrate specific embodiments and demonstrate the utility of the present invention. Experimental Section Example I: Synthesis and in vitro binding assessment of synthetic BBN analogues employing hydrocarbon chain spacers A. Synthesis: Many BBN analogues were synthesized by Solid Phase Peptide Synthesis (SPPS). Each peptide was prepared by SPPS using an Applied Biosystems Model 432 A peptide synthesizer. After cleavage of each BBN analogue from the resin using Trifluoracetic acid (TFA), the peptides were purified by C 18 reversed-phase HPLC using a Vydac HS54 column and CH 3 CN/H 2 0 containing 0.1% TFA as the mobile phase. After collection of the fraction containing the desired BBN peptide (approx. 80- 90% yield in most cases), the solvent was evaporated. The identity of each BBN peptide was confirmed by FAB -mass spectrometry, Department of Chemistry - Washington University, St. Louis, MO. Various amino acid sequences (in some cases including different chemical moieties) were conjugated to the N-terminal end of the BBN binding region (i.e., to BBN-8 or Trp 8 ). BBN analogue numbers 9,15, 15i, 16, 16i and 18 were synthesized as examples of N-terminal modified peptides as shown in Figure 5. Various tethered N-terminal (via Trp 8 ) BBN analogues were also synthesized by SPPS as exemplified by BBN-40, BBN-41 , BBN-42, BBN-43, BBN-44, BBN-45, and BBN-49 as shown in Figure 6. In these particular tethered peptides, a Glu residue was attached to Trp 8 followed by attachment of FmOC protected terminal amine groups separated from a -COOH group by 3-, 4-, 5-, 6-, 8- and 11 -carbon chain (CH) spacers (Figure 6). These FmOC protected acids were added as the terminal step during the SPPS cycle. As described previously, each of the BBN analogues was purified by reversed-phase HPLC and characterized by high resolution Mass Spectroscopy. Peptide 49 employed only glutamine as the spacer group. The [16]aneS 4 macrocyclic ligand was conjugated to selected tethered BBN analogues shown in Figure 6. The -OCH 2 COOH group on the [16]aneS 4 macrocycle derivative was activated via HOBt/HBTU so that it efficiently formed an amide bond with the terminal NH 2 group on the spacer side arm (following deprotection). The corresponding [16]aneS 4 tethered BBN derivatives were produced and examples of 4 of these derivatives (i.e., BBN-22, -37, -46 and -47) are shown in Figure 7. As previously described, each [16]aneS 4 BBN derivative was purified by reversed phase HPLC and characterized by FAB Mass Spectroscopy. B. In Vitro Binding Affinities The binding affinities of the synthetic BBN derivatives were assessed for GRP receptors on Swiss 3T3 cells and, in some cases, on a variety of human cancer cell lines, that express GRP receptors. The IC 50 's of each derivative was determined relative to (i.e., in competition with) 125 I-Tyr 4 -BBN (the K d for 125 I-Tyr 4 -BBN for GRP receptors in Swiss 3T3 cells is reported to be 1.6+0.4 nM) [Zueht et al., 1991]. The cell binding assay methods used to measure the IC 50 's is standard and was used by techniques previously reported [Jensen et al., 1993; Cai et al., 1994; Cai et al., 1992] . The methods used for determining IC 50 's with all GRP receptor binding of GRP receptors on all cell lines was similar. The specific method used to measure IC 50 's on Swiss 3T3 cells is briefly described as follows: Swiss 3T3 mouse fibroblasts are grown to confluence in 48 well microtiter plates. An incubation media was prepared consisting of HEPES (11.916g/l), NaCl (7.598 g/1), KC1 (0.574 g/1), MgCl 2 (1.106 g/1), EGTA (0.380 g/1), BSA (5.0 g/1), chymostatin (0.002 g/1), soybean trypsin inhibitor (0.200 g/1), and bacitracin (0.050 g/1). The growth media was removed, the cells were washed twice with incubation media, and incubation media was returned to the cells. 125 I-Tyr 4 -BBN (0.01 uCi) was added to each well in the presence of increasing concentrations of the appropriate competitive peptide. Typical concentrations of displacing peptide ranged from 10 "12 to 10 "5 moles of displacing ligand per well. The cells were incubated at 37°C for forty minutes in a 95%O 2 /5%CO 2 humidified environment. At forty minutes post initiation of the incubation, the medium was discarded, and the cells were washed twice with cold incubation media. The cells were harvested from the wells following incubation in a trypsin/EDTA solution for five minutes at 37°C. Subsequently, the radioactivity, per well, was determined and the maximum % total uptake of the radiolabeled peptide was determined and normalized to 100%. C. Results of Binding Affinity Measurements The IC 50 values measured for the BBN derivatives synthesized in accordance with this invention showed that appending a peptide side chain and other moieties via the N-terminal BBN-8 residue (i.e., Trp 8 ) produced widely varying IC 50 values. For example, see IC 50 values shown for BBN 11, 15i, 16i, and 18 in Figures 5 and 8. The observations are consistent with previous reports showing highly variable IC 50 values when derivatizing BBN(8-13) or BBN(8-14) with a predominantly short chain of amino acid residues [Hoffken, 1994]. In contrast, when a hydrocarbon spacer of 3- to 11 -carbons was appended between BBN(7-14) and the [16]aneS 4 macrocycle, the IC 50 's were found to be surprisingly relatively constant and in the 1-5 nM range (i.e., see IC 50 values for BBN-22, -37, -46 and -47 as shown in Figure 7). These data suggest that using relatively simple spacer groups to extend ligands some distance from the BBN binding region [e.g., BBN(8-14)] can produce derivatives that maintain binding affinities in the 1-5 nmolar range. P. Cell Binding Studies Results illustrated in Figure 9 show that when the RhCl 2 - [16]aneS 4 complex separated from Trp 8 by only a glutamine (Glu 7 ), the IC 50 of this conjugate (i.e., Rh-BBN-22) was 37.5 nM. However, when a five (5) carbon spacer or an eight (8) carbon spacer was present (i.e., Rh- BBN-37 and Rh-BBN-47), the IC 50 's remained below 5 nM as shown in Figure 9. These data demonstrate that a straight chain spacer (along with glu 7 ) to move the +1 charged Rh-S 4 -chelate away from the BBN binding region will result in a metallated BBN analogue with sufficiently high binding affinities to GRP receptors for in vivo tumor targeting applications. E. 105 Radiolabeled BBN Analogues The 105 Rh conjugates of BBN-22, BBN-37, BBN-46 and BBN-47 were synthesized using a 105 Rh-chloride reagent from the Missouri University Research Reactor (MURR). This reagent was obtained as 105 Rh-chloride, a no-carrier-added (NCA) product, in 0.1 -1M HCl. The pH of this reagent was adjusted to 4-5 using 0.1-1.0 M NaOH dropwise and it was added to approximately 0.1 mg of the [16]aneS 4 - conjugated BBN derivatives in 0.9% aqueous NaCl and 10% ethanol. After the sample was heated at 80°C for one hour, the 105 Rh-BBN analogues were purified using HPLC. In each case, a NCA or high specific activity product was obtained since the non-metallated S 4 -BBN conjugates eluted at a retention time well after the 105 Rh-BBN conjugates eluted. For example, the retention time of 105 Rh-BBN-37 was 7.1 min while BBN-37 eluted at 10.5 min from a C-18-reversed phase column eluted with CH 3 CN/H 2 O containing 0.1% TFA as shown in Figure 10A-B. Example II: Retention of Rh-BBN Analogues in Cancer Cells Once the radiometal has been specifically "delivered" to cancer cells (e.g., employing the BBN binding moiety that specifically targets GRP receptors on the cell surface), it is necessary that a large percentage of the "delivered" radioactive atoms remain associated with the cells for a period time of hours or longer to make an effective radiopharmaceutical for effectively treating cancer. One way to achieve this association is to internalize the radiolabeled BBN conjugates within the cancer cell after binding to cell surface GRP receptors. In the past, all of the work with synthetic-BBN analogues for treatment of cancers focused on synthesizing and evaluating antagonists [Davis et al., 1992; Hoffken , 1994; Moody et al., 1996; Coy et al., 1988; Cai et al., 1994; Moody et al., 1995; Leban et al., 1994; Cai et al., 1992]. After evaluating synthetic BBN analogues that would be predicted to be either agonists or antagonists, applicants found that derivatives of BBN(8-14) (i.e., those with the methionine or amidated methionine at BBN-14) are rapidly internalized (i.e., in less than two minutes) after binding to the cell surface GRP receptors. Several radiolabeled BBN(8-14) analogues that were studied to determine their internalization and intracellular trapping efficiencies were radioiodinated (i.e., 125 I) derivatives. The results of these studies demonstrated that despite rapid internalization after 125 I-labeled BBN analogue binding to GRP receptors in Swiss 3T3 cells, the 125 I was rapidly expelled from the cells [Hoffman et al., 1997] as shown in Figure 11. Thus, these 125 I-BBN derivatives were not suitable for further development. In contrast, the 105 Rh-BBN(8-14) derivatives that bind to GRP receptors are not only rapidly internalized, but there is a large percentage of the 105 Rh activity that remains trapped within the cells for hours (and in some cell lines > twenty four hours). This observation indicates that these radiometallated BBN derivatives have real utility as radiopharmaceuticals for in vivo targeting of neoplasms expressing GRP receptors. Experiments designed to determine the fraction of a radiotracer internalized within cells were performed by adding excess I25 I- or 105 Rh-BBN derivatives to the cell incubation medium. After establishment of equilibrium after a forty minute incubation, the media surrounding the cells was removed and the cells were washed with fresh media containing no radioactivity. After washing, the quantity of radioactivity associated with the cells was determined (i.e., total counts per min (TCPM) of 125 I or 105 Rh associated with the cells). The cells were then incubated in a 0.2M acetic acid solution (pH 2.5) which caused the surface proteins (incl., GRP receptors) to denature and release all surface bound radioactive materials. After removing this buffer and washing, the cells were counted again. The counts per minute (c.p.m.) associated with the cells at that point were only related to the 125 I or 105 Rh that remained trapped inside of the cells. To determine intracellular retention, a similar method was employed. However, after washing the cells with fresh (non-radioactive) incubation media, the cells were incubated in the fresh media at different time periods after washing away all extracellular 125 I- or 105 Rh-BBN analogues. After each time period, the methods used to determine TOTAL c.p.m. and intracellular c.p.m. after washing with a 0.2M acetic acid solution at pH 2.5 were the same as described above and the percent 125 I or 105 Rh remaining trapped inside of the cells was calculated. Figure 12 is a graph of results of efflux experiments using Swiss 3T3 cells with 125 I-Lys 3 -BBN. The results show that there is rapid efflux of the 125 I from inside of these cells with less than 50% retained at fifteen minutes and by sixty minutes, less than 20% remained as shown in Figure 12. In contrast, studies with all of the 105 Rh-[l 6]aneS 4 -BBN agonist derivatives that are internalized inside of the cells showed substantial intracellular retention of 105 Rh by the GRP receptor expressing cells. For example, results of studies using 105 Rh-BBN-37 (see Figure 9) in conjunction with Swiss 3T3 cells showed that approximately 50% of the 105 Rh activity remains associated with the cells at sixty minutes post- washing and approximately 30% of 105 Rh remained inside of the cells after four hours as shown in Figure 13. Note that at least 5% of the 105 Rh is surface bound at > sixty minutes. The 105 Rh-BBN derivatives shown in Figure 9 all have an amidated methionine at position BBN- 14 and are expected to be agonists [Jensen et al., 1993]. Therefore, they would be predicted to rapidly internalize after binding to GRP receptors on the cell surface [Reile et al., 1994; Bjisterbosch et al., 1995; Smythe et al., 1991], which was confirmed by applicants' data. Referring to Figure 14, 105 Rh-BBN-61, a BBN analogue with no amino acid at position BBN- 14 (i.e., a 105 Rh- BBN(8-13) derivative), was synthesized and studied. This BBN analogue has a high bonding affinity (i.e., IC 50 = 30 nM). This type of derivative is expected to be an antagonist and as such will not internalize [Jensen et al., 1993; Smythe et al, 1991]. Results of efflux studies with 105 Rh-BBN-61 using Swiss 3T3 cells showed that immediately following washing with fresh incubation buffer (i.e., t=0), essentially all of the 105 Rh associated with these cells is on the cell surface, as expected. Furthermore, after only one hour of incubation, less than 10% remained associated with these cells in any fashion (see Figures 15 and 16). These data indicate that 105 Rh-antagonists with structures similar to the 105 Rh-BBN agonists (i.e., those shown in Figure 9) are not good candidates for development of radiopharmaceuticals since they are neither trapped in nor on the GRP receptor expressing cells to nearly the same extent as the radiometallated BBN agonists. EXAMPLE III: Human Cancer Cell Line Studies In vitro cell binding studies of 105 Rh-BBN-37 with two different human cancer cell lines that express GRP receptors (i.e., the PC- 3 and CF-PAC1 cell lines), which are tumor cells derived from patients with prostate CA and pancreatic CA, as shown in Figures 17A-B and 18 A-B, respectively ) were performed. Results of these studies demonstrated consistency with 105 Rh-BBN-37 binding and retention studies using Swiss 3T3 cells. Specifically, the binding affinity of Rh- BBN-37 was high (i.e., IC 50 = 7 nM) with both human cancer cell lines as shown in Table 1. In addition, in all cells, the majority of the 105 Rh-BBN- 37 was internalized and perhaps a major unexpected result was that the retention of the 105 Rh-tracer inside of the cells was significantly better than retention in Swiss 3T3 cells as shown in Figures 17 and 18. For example, it is particularly remarkable that the percentage of 105 Rh-BBN-37 that remained associated with both the CFPAC-1 and PC-3 cell line was >80% at two hours after removing the extracellular activity by washing with fresh incubation buffer (see Figures 17 and 18). EXAMPLE IV: 7N VIVO STUDIES Biodistribution studies were performed by intravenous (IN.) injection of either 105 Rh-BBΝ-22 or 105 Rh-BBN-37 into normal mice. In these studies, unanesthetized CF-1 mice (15-22g, body wt.) were injected IN. via the tail vein with between one (1) to five (5) uCi (37-185 KBq) of the 105 Rh- labeled agent. Organs, body fluids and tissues were excised from animals sacrificed at 30, 60 and 120 minutes post-injection (PI). The tissues were weighed, washed in saline (when appropriate) and counted in a Νal well counter. These data were then used to determine the percent injected dose (% ID) in an organ or fluid and the %ID per gram. The whole blood volume of each animal was estimated to be 6.5 percent of the body weight. Results of these studies are summarized in Tables 2 and 3. Results from these studies showed that both the 105 Rh- BBΝ-22 and 105 Rh-BBN-37 were cleared from the blood stream, predominantly via the kidney into the urine. Specifically, 68.4 ± 6.6% and 62.3 ± 5.8% of the ID was found in urine at two hours PI of 105 Rh- BBN-22 and 105 Rh-BBN-37, respectively (see Tables 2 and 3). An unexpected finding was that the % ID of I05 Rh that remained deposited in the kidneys of these animals was only 2.4 ± 0.6 % ID and 4.6 ± 1.3 % ID at two hours PI of 105 Rh-BBN-22 and 105 Rh-BBN-37 (see Tables 2 and 3). This is much less than would be expected from previously reported data where radiometallated peptides and small proteins have exhibited renal retention of the radiometal that is > 10% ID and usually much > 10% [Duncan et al., 1997]. The reason for reduced renal retention of 105 Rh- BBN analogues is not known, however, this result demonstrates a substantial improvement over existing radiometallated peptides. Biodistribution studies also demonstrated another important in vivo property of these radiometallated BBN analogues. Both 105 Rh-BBN-22 and 105 Rh-BBN-37 are efficiently cleared from organs and tissues that do not express GRP receptors (or those that do not have their GRP-receptors accessible to circulating blood). The biodistribution studies in mice demonstrated specific uptake of 105 Rh-BBN-22 and 105 Rh- BBN-37 in the pancreas while other non-excretory organs or tissues (i.e., heart, brain, lung, muscle, spleen) exhibited no uptake or retention (Tables 2 and 3). Both 105 Rh-BBN-22 and I05 Rh-BBN-37 were removed from the blood stream by both the liver and kidneys with a large fraction of the 105 Rh removed by these routes being excreted into the intestines and the bladder, respectively. It is important to note that the % ID/gm in the pancreas of 105 Rh-BBN-22 and 105 Rh-BBN-37 was 3.9 ± 1.3 % and 9.9 + 5.4 %, respectively at 2 hr, PI. Thus, the ratios of % ID/gm of 105 Rh- BBN-22 in the pancreas relative to muscle and blood were 16.2 and 7.6, respectively. The ratios of% ID/gm of 105 Rh-BBN-37 in the pancreas relative to muscle and blood were 25.4 and 29.1, respectively. These data demonstrated selective in vivo targeting of these radiometallated BBN analogues to cells expressing GRP receptors [Zhu et al., 1991; Qin et al., 1994] and efficient clearance from non-target tissues. If cancer cells that express GRP receptors are present in the body, these results indicate radiometallated BBN analogues will be able to target them with a selectivity similar to the pancreatic cells. A comparison of the pancreatic uptake and retention of 105 Rh-BBN-22 with 105 Rh-BBN-37 demonstrated that 105 Rh-BBN-37 deposits in the pancreas with a 2-fold better efficiency than 105 Rh-BBN-22 (i.e., 3.6 ± 1.2% ID and 2.3 ± 1.0 % ID) for 105 Rh-BBN-37 at one and two hours PI, respectively, vs. 1.2 ± 0.5% ID and 1.0 ± 0.1% ID for 105 Rh- BBN-22 at one and two hours PI). This data is consistent with the >2-fold higher uptake and retention of 105 Rh-BBN- 37 found in the in vitro studies shown in Figure 16. Example V: Synthesis and in vitro binding measurement of synthetic BBN conjugate analogues employing amino acid chain spacers A. Synthesis Five BBN analogues were synthesized by SPPS in which between 2 to 6 amino acid spacer groups were inserted to separate a S 4 -macrocyclic chelator from the N-terminal trp 8 on BBN(8-14) (Figure 19). Each peptide was prepared by SPPS using an Applied Biosystems Model 432A peptide synthesizer. After cleavage of each BBN analogue from the resin using Trifluoracetic acid (TFA), the peptides were purified by C 18 reversed-phase HPLC using a Vydac HS54 column and CH 3 CN/H 2 0 containing 0.1% TFA as the mobile phase. After collection of the fraction containing the desired BBN peptide, the solvent was evaporated. The identity of each BBN peptide was confirmed by FAB-mass spectrometry (Department of Chemistry - Washington University, St. Louis, MO). Various amino acid sequences (in some cases containing different R group moieties) were conjugated to the N-terminal end of the BBN binding region (i.e., to BBN-8 or Trp 8 ). BBN analogue numbers 96, 97, 98, 99 and 101 were synthesized as examples of N-terminal modified peptides in which the [16]aneS 4 macrocycle BFCA was separated from tip 8 on BBN(8-14) by various amino acid sequences as shown in Figure 19. The [16]aneS 4 macrocyclic ligand was conjugated to selected tethered BBN analogues. The -OCH 2 COOH group on the [16]andS 4 macrocycle derivative was activated via HOBt/HBTU so that it efficiently formed an amide bond with the terminal NH2 group on the spacer side arm (following deprotection). The corresponding [16]aneS 4 tethered BBN derivatives were produced and examples of 5 of these derivatives (i.e., BBN-96, 97, 98, 99 and 101) are shown in Figure 19. As previously described, each [16]aneS 4 BBN derivative was purified by reversed phase HPLC and characterized by FAB Mass Spectroscopy. B. In Vitro Binding Affinities The binding affinities of the synthetic BBN derivatives were assessed for GRP receptors on Swiss 3T3 cells, PC-3 cells and CF PAC-1 cells. The IC 50 's of each of derivative was determined relative to (i.e., in competition with) 125 I-Tyr 4 -BBN. The cell binding assay methods used to measure the IC 50 's is standard and was used by techniques previously reported [Jensen et al., 1993; Cai et al., 1992; Cai et al., 1994]. The methods used for determining IC 50 's with all BBN analogue binding to GRP repectors present on all three cell lines was similar. The specific method used to measure IC 50 's on Swiss 3T3 cells is briefly described as follows: Swiss 3T3 mouse fibroblasts are grown to confluence in 48 well microliter plates. An incubation media was prepared consisting of HEPES (11.916g/l), NaCl (7.598 g/1), KC1 (0.574 g/1), MgCl 2 (1.106 g/1), EGTA (0.380 g/1), BSA (5.0 g/1), chymostatin (0.002 g/1), soybean trypsin inhibitor (0.200 g/1), and bacitracin (0.050 g/1). The growth media was removed, the cells were washed twice with incubation media, and incubation media was returned to the cells. I25 I-Tyr 4 -BBN (0.01 μCi) was added to each well in the presence of increasing concentrations of the appropriate competitive peptide. Typical concentrations of displacing peptide ranged from 10 "12 to 10 "5 moles of displacing ligand per well. The cells were incubated at 37°C for forty minutes in a 95% O 2 /5% CO 2 humidified environment. At forty minutes post initiation of the incubation, the medium was discarded, and the cells were washed twice with cold incubation media. The cells were harvested from the wells following incubation in a trypsin/EDTA solution for five minutes at 37°C. Subsequently, the radioactivity, per well, was determined and the maximum % total uptake of the radiolabeled peptide was determined and normalized to 100%. A similar procedure was used in performing cell binding assays with both the PC-3 and CF a -PAC-l human cancer cell lines. C. Results of Binding Affinity Measurements The IC 50 values measured for the BBN derivatives synthesized in accordance with this invention showed that appending a chelator via amino acid chain spacer groups via the N-terminal BBN-8 residue (i.e., Tip 8 ) produced a variation of IC 50 values. For example, see IC 50 values shown for BBN 96, 97, 98 and 101 in Figure 19. The observations are consistent with previous reports showing variable IC 50 values when derivatizing BBH(8-13) with a predominantly short chain of amino acid residues [Hoffken, 1994]. When the amino acid spacer groups used in BBN-98, 99 and 101 were appended between BBN(7-14) and the [16]aneS 4 macrocyle, the IC 50 's were found to be surprisingly constant and in the 1-6 nM range for all three cell lines (i.e., see IC 50 values shown in Figure 19). These data suggest that using relatively simple spacer groups composed entirely of selected amino acid sequences to extend ligands some distance from the BBN region [e.g., BBN(8-14) can produce derivatives that maintain binding affinities in the 1-6 nmolar range. P. Cell Binding Studies with Rh-BBN-Coniugates Results illustrated in Figure 20 show that when the corresponding RhCl 2 [16]aneS 4 complex was separated from Trp 8 on BBH(8-14) by the four different amino acid spacer groups (see Figure 20), the IC 50 's of all four analogues (i.e., BBN-97, -98, -99, -101) were between 0.73 and 5.29 nmolar with GRP receptors on the PC-3 and CF PAC-1 cell lines. The IC 50 's for these same Rh-BBN conjugates were somewhat higher with the Swiss 3T3 cell line (Figure 20). These data demonstrate that amino acid chain with spacer groups used to move the +1 charged Rh-S 4 -chelate away from the BBN binding region will result in a metallated BBN analogue with sufficiently high binding affinities to GRP receptors for in vivo tumor targeting applications. Example VI: Synthesis and in vitro binding assessment of a — Tc-labeled synthetic BBN analogue A. Synthesis Several tetradentate chelating frameworks have been used to form stable 99m Tc or 188 Re labeled peptide and protein conjugates [Eckelman, 1995; Li et al., 1996b; Parker, 1990; Lister- James et al., 1997]. Many of these ligand systems contain at least one thiol (-SH) donor group to maximize rates of formation and stability (both in vitro and in vivo) of the resultant Tc(V) or Re(V) complexes [Parker, 1990; Eckelman, 1995]. Results from a recent report indicates that the bifunctional chelating agent (BFCA) (dimethylglycyl-L-seryl-L-cyteinyl- glycinamide (N 3 S-BFCA) is capable of forming a well-defined complex with ReO +3 and TcO +3 [Wong et al, 1997]. Since this ligand framework can be synthesized by SPPS techniques, this N 3 S-BFCA was selected for use in forming of Tc-99m-BBN-analogue conjugates. Three different N 3 S-BFCA conjugates of BBN(7-14) were synthesized (BBN-120, -121 and - 122) as shown in Figure 21 by SPPS. BBN- 120, BBN- 121 and BBN- 122 represent a series of analogues where the N 3 S-BFCA is separated from the BBN(7-14) sequence by a 3, 5 and 8 carbon spacer groups (Figure 21). Each peptide was synthesized and purified using the SPPS and chromatographic procedures outlined in Example 1. The thiol group on cystein was protected using the ACM group, which is not cleaved during cleavage of these BBN-conjugates from the resin using TFA. The identity of BBN-120, -121 and -122 was confirmed by FAB mass spectrometry. Synthesis and purification of the N 3 S-BFCA could also be readily accomplished using SPPS methods, followed by HPLC purification (see Example 1). The ACM group was used to protect the thiol group on cysteine during synthesis and cleavage from the resin. B. In Vitro Binding Affinities Synthesis of 99m Tc-BBN-122 (Figure 22) was prepared by two methods [i.e., (1) by transchelation of 99m TcO +3 from 99m Tc-gluconate or (2) by formation of the "preformed" 99m Tc-BFCA complex followed by -COOH activation with tetrafiuorophenyl and subsequent reaction with the C 5 -carbon spacer group appended to BBN(7-14)]. In both cases, the 99m Tc-labeled peptide formed is shown in Figure 22. The structure of this Tc-BBN-122 conjugate was determined by using non-radioactive Re(the chemical congener of Tc). In these studies, the "preformed" ReO +3 complex with the N 3 S-BFCA was prepared by reduction of ReO 4 ; with SnCl 2 in the presence of excess N 3 S-BFCA dissolved in sodium phosphate buffered water at pH 6-6.5 by a method previously published [Wong et al., 1997]. After purification of the ReO-N 3 S-BFCA complex, the structure of this chelate was shown (by Mass-Spect) to be identical to that previously reported [Wong et al., 1997]. The ReO-N 3 -S-BFCA complex was converted to the activated trifluorophenyl (TFP) ester by adding 10 mg of the complex to 6 mg (dry) EDC and the 50 μl of TFP. After the solution was vortexed for one minute, CH 3 CN was added until disappearance of cloudiness. The solution was incubated for one hour at RT and purified by reversed-phase HPLC. To prepare the ReO-N 3 S-BFCA complex BBN- 122 conjugate (Figure 22), one μl of the HPLC fraction containing the ReO-N 3 S-BFCA complex was added to a solution containing 1 mg of the C 8 -tethered BBN(7-14) peptide in 0.2 N NaHCO 3 at pH 9.0. After incubation of this solution for one hour at RT, the sample was analyzed and purified by reversed-phase HPLC. The yield of Re-BBN-122 was approximately 30- 35%. The method for preparation of the corresponding 99m Tc- BBN-122 conjugate, using the "preformed" 99m TcO-N 3 S-BFCA complex, was the same as described above with the "preformed" ReO-N 3 S-BFCA complex. In this case, 99m Tc0 4 , from a 99 Mo/" m Tc generator, was reduced with an aqueous saturated stannous tartrate solution in the presence of excess N 3 S-BFCA. The yields of the 99m Tc-BBN-122 product using this "preformed" method were approximately 30-40%. Reversed phase HPLC analysis of the 99mTc-BBN-122, using the same gradient elution program 1 as used for analysis of the Re-BBN-122 conjugate, showed that 1 Gradient elution program used in these studies was as follows. Flow 1.5 ml/minute Solvent A = HO with 0.1% TFA Solvent B = CHCN with 0.1% TFA both the 99m Tc-BBN-122 and 188 Re-BBN-122 had the same retention time (i.e., 14.2-14.4 min) (See Figure 22). This provides strong evidence that the structure of both the 99m Tc-BBN-122 and Re-BBN-122 are identical. The binding affinities of BBN- 122 and Re-BBN-122 were assessed for GRP receptors on Swiss 3T3 cells, PC-3 cells and CFPAC-1 cells that express GRP receptors. The IC 50 's of each derivative was determined relative to (i.e., in competition with) I25 I-Tyr 4 -BBN (the K d for 125 I-Tyr 4 -BBN for GRP receptors in Swiss 3T3 cells is reported to be 1.6+0.4nM) [Zhu et al., 1991]. The cell binding assay methods used to measure the IC 50 's is standard and was used by techniques previously reported [Leban et al., 1994; Cai et al, 1994; Cai et al., 1992]. The methods used for determining IC 50 's with all GRP receptor binding of GRP receptors on all cell lines was similar and has been described previously for the other BBN-analogues and Rh-BBN analogues described in this document. C. Results of Binding Affinity Measurements The IC 50 values measured for BBN-122 and Re-BBN-122 synthesized in accordance with this invention showed that appending an Time (minutes ' ) %A/%B 0 95/5 25 30/70 35 95/5 8-carbon hydrocarbon chain spacer linked to the N 2 S,-BFCA and the corresponding Re complex (i.e., Trp 8 ) produced BBN conjugates with IC 50 values in a 1-5 nmolar range (See Table A). When 99m Tc-BBN-122 was incubated with these same cells, it was shown that > nmolar concentrations of BBN displaced this 99m Tc conjugate by > 90%. This result demonstrates that 99m Tc-BBN-122 has high and specific binding affinity for GRP receptors. These data suggest that using relatively simple spacer groups to extend the N 3 S ligand framework and the corresponding Tc-or Re-N 3 S„ complexes some distance from the BBN binding region can produce derivatives that maintain binding affinities in the 1-5 nmolar range. TABLE A. Summary of IC 50 values for GRP receptor binding for the non-metallated BBN-122 conjugate or the Re-BBN-122 conjugate in two cell lines (PC-3 and CF-PAC-1 cell lines that express GRP receptors). The IC 50 values were measured using cell binding assays relative to 125 I- Tyr 4 -BBN. Example VII: Retention of 99mTc-BBN-122 in Human Cancer Cells PC-3 and CF-PAC-1 cells ' ) Once the radiometal has been specifically "delivered" to cancer cells (e.g., employing the BBN binding moiety that specifically targets GRP receptors on the cell surface), it is necessary that a large percentage of the "delivered" radioactive atoms remain associated with the cells for a period time of hours or longer to make an effective radiopharmaceutical for effectively treating cancer. One way to achieve this association is to internalize the radiolabeled BBN conjugates within the cancer cell after binding to cell surface GRP receptors. Experiments designed to determine the fraction 99m Tc- BBN-122 internalized within cells were performed by the same method previously described for 105 Rh-BBN-37. Briefly, excess 99m Tc-BBN-122 was added to PC-3 or CFPAC-1 cell incubation media and allowed to establish equilibrium after a forty minute incubation. The media surrounding the cells was removed and the cells were washed with fresh media containing no radioactivity. After washing, the quantity of radioactivity associated with the cells was determined (i.e., total counts per min 99m Tc associated with cells). The PC-3 and CFPAC-1 cells were then incubated in a 0.2M acetic acid solution (pH2.5) which caused the surface proteins (including GRP receptors) to denature and release all surface bound radioactive materials. After removing this buffer and washing, the cells were counted again. The counts per minute (c.p.m.) associated with the cells at that point were only related to the 99m Tc that remained trapped inside of the PC-3 or CFPAC-1 cells. To determine intracellular retention of 99m Tc activity, a similar method was employed. However, after washing the cells with fresh (non-radioactive) incubation media, the cells were incubated in the fresh media at different time period after washing away all extracellular 99m Tc-BBN-122. After each time interval, the methods used to determine total c.p.m. and intracellular c.p.m. by washing with a 0.2M acetic acid solution at pH 2.5. Studies with the 99mTc-BBN- 122 agonist show that it is internalized inside of the PC-3 and CFPAC-1 cells (Figures 23-26) and that substantial intracellular retention of 99m Tc by the GRP receptor expressing cells occurs. For example, results of studies using 99m Tc-BBN- 122 in conjunction with PC-3 cells showed a high rate of internalization (Figure 23) and that approximately 75% of the 99m Tc activity remains associated with the cells at ninety minutes post-washing (Figure 25). Almost all of this 99m Tc cell-associated activity is inside of the PC-3 cells. Similar results were also found with the CFPAC 1 cells where there is also a high rate of 99m Tc-BBN-122 internalization (Figure 24) and relatively slow efflux of 99m Tc from the cells (i.e., 50-60% retention at 120 min post-washing (Figure 26). The 99m Tc-BBN-122 peptide conjugate shown in Figure 22 has an amidated methionine at position BBN- 14 and is expected to be an agonists [Jensen et al., 1993]. Therefore, it would be predicted to rapidly internalize after binding to GRP receptors on the cell surface [Bjisterbosch et al., 1995; Smythe et al., 1991], which is confirmed by applicants' data in Figure 23-26. Example VIII: In Vivo Studies Biodistribution studies were performed by intravenous (IN.) injection of 99m Tc-BBΝ-122 into normal mice. In these studies, unanesthetized CF-1 mice (15-22g, body wt.) were injected IN. via the tail vein with between one (1) to five (5) μCi (37-185 KBq) of 99m Tc- BBN-122. Organs, body fluids and tissues were excised from animals sacrificed at 0.5, 1 , 4 and 24 hours post-injection (PI). The tissues were weighed, washed in saline (when appropriate) and counted in a Nal well counter. These data were then used to determine the percent injected dose (% ID) in an organ or fluid and the % ID) per gram. The whole blood volume of each animal was estimated to be 6.5 percent of the body weight. Results of these studies are summarized in Tables B and C. Results from these studies showed that 99mTc-BBN-122 is cleared from the blood stream predominantly via the hepatobiliary pathway shaving about 35% of the 99m Tc-activity cleared via the kidney into the urine. Specifically, 33.79±1.76% of the ID was found in urine at one hour PI (Table B). The retention of 99m Tc activity in the kidneys and liver is very low (Table B). This is much less than would be expected from previously reported data where radiometallated peptides and small proteins have exhibited renal retention of the radiometal that is > 10% IP and usually much > 10% [Puncan et al., 1997]. The reason for reduced renal retention of 99m Tc-BBN-122 is not known, however, this result demonstrates a substantial improvement over existing radiometallated peptides. Biodistribution studies also demonstrated another important in vivo property of 99m Tc-BBN-122 in that it is efficiently cleared from organs and tissues that do not express GRP receptors (or those that do not have their GRP-receptors accessible to circulating blood). The biodistribution studies in mice demonstrated specific uptake of 99m Tc-BBN-122 in the pancreas while other non-excretory organs or tissues (i.e., heart, brain, lung, muscle, spleen) exhibited no uptake or retention. 99m Tc-BBN-122 is removed from the blood stream by both the liver and kidneys with a large fraction of the 99mTc removed by these routes being excreted into the intestines and the bladder, respectively. It is important to note that the % IP/gm in the pancreas of 99m Tc-BBN-122 is 12.63%/gm at 1 hour and drops to only 5.05% at the 4 hour PI (Table C). Thus, the ratios of % IP/gm of 99m Tc-BBN-122 in the pancreas relative to muscle and blood were 92.2 and 14.78 at 4 hour PI, respectively. These data demonstrated selective in vivo targeting of this 99m Tc-labeled BBN analogue to cells expressing GRP receptors [Zhu et al., 1991; Qin et al., 1994] and efficient clearance from non-target tissues. If cancer cells that express GRP receptors are present in the body, these results indicate 99mTc-BBN analogues will be able to target them with a selectivity similar to the pancreatic cells. Table B. Biodistribution of Wm Tc-BBN-122 in normal CF-1 mice at 0.5, 1, 4 and 24 hr post-IV injection. Results expressed as % IP/organ a. Each value in the table represents the mean and SD from 5 animals in each group. b. At 4 and 24 hr, feces containing "Tc had been excreted from each animal and the % ID in the urine was estimated to be approximately 60% of the ID. c. All other organs excised (incl. brain, heart, lung and spleen) showed < 0.10% at t -> 1 hr. d. % IP in the blood estimated assuming the whole blood volume is 6:5% of the body weight. Table C. Biodistribution of " m Tc-BBN-122 in normal CF-1 mice at 0.5, 1, 4 and 24 hr post I.V. injection. Results expressed as % IP/gm. a. Each value in the table represents the mean and SP from 5 animals in each group. b. % IP in the blood estimated assuming the whole blood volume is 6:5% of the body weight. Table P. Biodistribution of Wm Tc-BBN-122 in PC-3 tumor bearing SCIP mice at 1 , 4 and 24 hr post-I.V. injection. Results expressed as % IP/organ. a. Each value in the table represents the mean and SO from 5 animals in each group. b. At 4 and 24 hr, feces containing " m Tc had been excreted from each animal and the,. % IP in the urine was estimated to be approximately 60% of the IP. All other organs excised (incl. brain, heart, lung and spleen) showed < 0.10% at t > 1 hr. d. % IP in the blood estimated assuming the whole blood volume is 6:5% of the body weight. Table E. Biodistribution of " m Tc-BBN-122 in PC-3 tumor bearing SCIP mice at 1 , 4 and 24 hr post-I.V. injection. Results expressed as % IP/Gm. a. Each value in the table represents the mean and SP from 5 animals in each group. b. % IP in the blood estimated assuming the whole blood volume is 6:5% of the body weight. The invention has been described in an illustrative manner, and it is to be understood that the terminology which has been used is intended to be in the nature of words of description rather than of limitation. Obviously, many 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 than as specifically describe. Throughout this application, various publications are referenced by citation and number. Full citations for the publication are listed below, the disclosure of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains. 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Table 1 Binding Affinity of Rh-BBN-37 for GRP Receptors Expressed on Neopiasms X Complex υa Rh-Peptidβ22 U3 Rh-Peptide22 X' U3 Rh-Peptide22 30 min 1 hr 2 hr n-9 n-9 n-9 Organ (%Dose) Brain 0.08 0.04 0.06 ± 0.02 ± 0.01 ± 0.09 Blood 4.48 1.86 0.99 .+ 1.24 ± 0.38 ± 0.24 Heart 0.13 0.08 0.04 ± 0.03 ± 0.03 ± 0.04 Lung 0.25 0.20 0.15 _ 0.08 ± 0.09 ± 0.09 Liver 7.97 8.51 8.57 ± 2.85 ±_ 2.33 ± 2.04 Spleen 0.07 0.09 0.05 ^ ΣD ± 0.03 ± 0.08 ± 0.01 Stomach 1.11 0.59 0.30 ± 0.76 ± 0.21 φ ± 0.16 — t Large Intestine 0.73 3.21 8.91 +. 0.16 ± 3.38 ± 3.79 Small Intestine 6.29 6.98 3.48 ± 1.87 ± 1.87 -t 1.78 Kidneys 4;25 3.25 2.44 _ 1.33 ± 0.60 ± 0.64 Bladder 44.66 62.88 68.41 +. 7.29 ± 3.84 ± 6.63 Muscle 0.06 0.03 0.01 ±- 0.03 ± 0.03 ± 0.01 Pancreas 0.95 1.15 1.01 Carcass 32.90 12.62 6.37 ± 6.61 ± 4.77 ± 1.17 105 105 Rh-Peptide22 Rh-Pβptide22 Complex 105 Rh-Peρtide22 30 min 1 hr 2 hr n»9 n-9 n-9 Organ (VD/GM) Brain 0.21 0.14 0.16 0.07 0.08 0.28 Blood 2.22 1.02 0.51 0.40 0.22 0.11 Heart 0.92 0.64 0.38 0.25 0.20 0.33 Lung 1.44 1.24 0.92 ± 0.33 0.54 0.69 Liver 4.33 5.18 5.17 1.52 1.52 1.12 D H Spleen 0.86 1.10 0.84 O CO ± 0.38 0.65 0.53 &. 0 Stomach 2.46 1.53 0.71 O ± 1.65 0.74 0.33 § t Largo Intestine 0.78 4.42 10.10 o o 0.19 4.62 4.58 3 rt- H- Small Intestine 4.73 5.84 2.86 3 1.47 1.81 1.47 C ft) Kidneys 7.57 6.70 4.60 1.49 0.75 0.83 Muscle 0.53 0.61 0.24 0.32 0.97 0.24 Pancreas 3.12 4.31 3.88 0.99 1.98 1.25 Complex 105Rh-Pept37 105 Rh-Pept37 105 Rh-Pept37 30 min 1 hr 2 hr n-5 n-9 n-7 Organ (%Dose) Brain 0.03 0.07 0.03 0.01 0.11 ± 0.03 Blood 3.09 1.46 0.66 0.54 0.62 ± 0.26 Heart 0.12 0.05 0.04 0.03 0.03 ± 0.02 Lung 0.26 0.12 0.08 0.09 0.07 ± 0.11 Liver 1 Spleen Stomach Large Intestine 0.69 1.67 ± 2.25 Small Intestine 8.44 11.38 5.04 1.89 3.02 ± 2.27 Kidneys 7.82 6.04 4.57 2.52' 1.68 ± 1.29 Bladder 39.65 51.82 62.32 7.21 7.53 ± 5.78 Muscle 0.06 0.02 0.02 0.03 0.01 ± 0.02 Pancreas 2.73 3.63 2.25 1.14 1.22 ± 1.02- Carcass 24.35 9.81 6.37 7.69 2.91 ± 1.73 Complex 105 Rh-Pept37 105 Rh-Pept37 105 Rh-Pept37 30 min 1 hr 2 hr n-5 n*=9 n-7 Organ (%D/GM) Brain 0.10 0.26 0.10 0.05 0.41 0.09 Blood 1.60 0.72 0.34 0.30 0.31 0.15 Heart 0.92 0.38 0.28 0.26 0.21 0.17 Lung 1.52 0.76 0.46 0.48 0.47 0.50 σv Liver 7.31 7.65 6.30 vo 1.15 1.29 1.73 D H Spleen 2.18 1.59 1.05 O SB 1.17 0.71 0.44 co CD Ξ Stomach 1.53 1.63 2.18 0.67 1.17 2.35 δ CD 3 C Large Intestine 2.46 3.80 11.84 o o 0.70 2.42 4.39 3 ΓT H- Small .Intestine 5.69 7.85 3.81 3 1.26 1.87 2.01 C (D CL Kidneys 14.28 11.21 8.39 2.84 3.68 2.36 Muscle 0.73 0.20 0.39 0.39 0.14 0.38 Pancreas 14.02 15.54 9.91 3.23 6.21 5.35

Claims: CLAIMS What is claimed is: 1. A compound for use as a therapeutic or diagnostic radiopharmaceutical, said compound comprising a group capable of complexing a metal attached to a moiety capable of binding to a gastrin releasing peptide (GRP) receptor. 2. A compound as set forth in claim 1, wherein said moiety capable of binding to a gastrin releasing peptide receptor is a gastrin releasing peptide receptor agonist. 3. A compound as set forth in claim 2, wherein said gastrin releasing peptide receptor agonist includes a bombesin agonist binding moiety. 4. A compound as set forth in claim 1 , wherein said group capable of complexing a metal includes a chelating group. 5. A compound as set forth in claim 4, wherein said chelating group is attached to said bombesin agonist binding moiety by a spacer group. 6. A compound as set forth in claim 5 having a structure of the formula: X-Y-B wherein X is said group capable of complexing a metal; Y is said spacer group or covalent bond; and B is a bombesin agonist binding moiety. 7. A compound as set forth in claim 6, wherein Y is a C^C^ hydrocarbon chain. 8. A compound as set forth in claim 7, wherein Y is a C 3 -C 9 hydrocarbon chain. 9. A compound as set forth in claim 6, wherein Y includes at least one amino acid residue. 10. A compound as set forth in claim 9, wherein Y includes a L-Gln residue at the BBN-7 position. 11. A compound as set forth in claim 5, wherein said chelating group is attached to said bombesin agonist binding moiety at the N- terminal end of a peptide bombesin binding moiety. 12. A compound as set forth in claim 11, wherein said chelating group is attached to said peptide bombesin agonist binding moiety at amino acid residue 8 (tφ 8 ) of said bombesin agonist binding moiety. 13. A compound as set forth in claim 11 , wherein said spacer is attached to said bombesin agonist binding moiety at the N-terminal end of said bombesin agonist binding moiety. 14. A compound as set forth in claim 13, wherein said spacer is attached to said bombesin agonist binding moiety at amino acid residue 8 (D " or L " tφ 8 ) of said bombesin agonist binding moiety. 15. A compound as set forth in claim 1, wherein said metal is a diagnostically or therapeutically useful metal. 16. A compound as set forth in claim 15, wherein said transition metal is a metallic radioisotope selected form the group including γ and β emitting isotopes. 17. A compound as set forth in claim 16, wherein said metallic radioisotope is a radionuclide selected from the group including 186 Re, 188 Re, 99m Tc, 105 Rh, 199 Au, 153 Sm, 166 Ho and 90 Y. 18. A method as set forth in claim 16, wherein said metallic isotope includes oxides and nitrides thereof. 19. A compound as set forth in claim 4 wherein said chelating agent includes a multidentate chelating structure capable of foiming a highly stable complex with metals via coordinating atoms. 20. A compound as set forth in claim 19, wherein said chelating structure includes coordinating atoms S, N, O, or P. 21. A compound as set forth in claim 19, wherein said chelating structure is a macrocyclic compound including coordinating atoms. 22. A compound as set forth in claim 19, wherein said chelating structure is a S 4 chelator. 23. A compound as set forth in claim 19, wherein said compound is a N 4 chelator. 24. A compound as set forth in claim 19, wherein said compound is a N 2 S 2 chelator. 25. A compound as set forth in claim 19, wherein said compound is a NS 3 chelator. 26. A compound as set forth in claim 19, wherein said compound is a N 3 S chelator. 27. A compound as set forth in claim 3, wherein said compound has a binding affininity for the gastrin releasing peptide receptor that is approximately equal to or greater than that of native bombesin. 28. A method for treating a subject having a neoplastic disease, said method comprising the steps of: administering to the subject an effective amount of a pharmaceutical comprising a metal complexed with a chelating group attached to a moiety capable of specifically binding to a gastrin releasing peptide receptor. 29. A method as set forth in claim 28, wherein the moiety capable of binding to a gastrin releasing peptide receptor is a gastrin releasing peptide receptor agonist. 30. A method as set forth in claim 28 further including the step of contacting the radiopharmaceutical with a neoplastic cell. 31. A method as set forth in claim 30, wherein said contacting step is further defined as binding the radiopharmaceutical to gastrin releasing peptide receptors expressed on the neoplastic cell. 32. A method as set forth in claim 28 further including the step of internalizing the compound into the neoplastic cell. 33. A method as set forth in claim 28 further including the step of retaining the compound within the neoplastic cell for a period of time sufficient to initiate death of the neoplastic cell or provide a diagnostic image of the tumors. 34. A method as set forth in claim 29, wherein the gastrin releasing peptide receptor agonist includes a bombesin agonist binding moiety. 35. A method as set forth in claim 34, wherein the chelated metal is attached to the bombesin agonist binding moiety by a spacer group. 36. A method as set forth in claim 34, wherein the compound has the structure of the formula: X-Y-B wherein X is the group capable of binding a metal; Y is the spacer group or a covalent bond and B is a bombesin agonist binding moiety. 37. A method forth in claim 36, wherein Y is a C,-C 10 hydrocarbon chain. 38. A method as set forth in claim 37, wherein Y is a C 3 -C 9 hydrocarbon chain. 39. A method as set forth in claim 36, wherein Y includes at least one amino acid residue. 40. A method set forth in claim 39, wherein Y includes a L- Gln residue at the BBN-7 position. 41. A method as set forth in claim 36, wherein the chelating group is attached to peptide bombesin agonist binding moiety at the N-terminal end of the bombesin agonist binding moiety. 42. A method as set forth in claim 41 , wherein the chelating group is attached to the bombesin agonist binding moiety to amino acid residue 8 (D " or L " tφ 8 ) of the bombesin agonist binding moiety. 43. A method as set forth in claim 41, wherein the spacer is attached to the bombesin agonist binding moiety at the N-terminal end of the bombesin agonist binding moiety. 44. A method as set forth in claim 28, wherein the transition metal is a diagnostically or therapeutically useful radioactive metal. 45. A method as set forth in claim 44, wherein the metal is a metallic radioisotope selected form the group including γ and β emitting isotopes. 46. A method as set forth in claim 45, wherein the metallic radioisotope is a radionuclide selected from the group including 186 Re, 188 Re, 99ra Tc, 105 Rh, 199 Au, 153 Sm, 166 Ho and 90 Y. 47. A method as set forth in claim 46, wherein said metallic radioisotope includes oxides and nitrides thereof. 48. A compound as set forth in claim 28 wherein said chelating agent includes a multidentate chelating structure capable of forming a highly stable complex with metals via coordinating atoms. 49. A method as set forth in claim 48, wherein said chelating structure includes coordinating atoms S, N, O, or P. 50. A method as set forth in claim 48, wherein the chelating structure is a macrocyclic compound including coordinating atoms. 51. A method as set forth in claim 48, wherein said compound s a S 4 chelator. 52. A method as set forth in claim 48, wherein said compound s a N 4 chelator. 53. A method as set forth in claim 48, wherein said compound s a N 2 S 2 chelator. 54. A method as set forth in claim 48, wherein said compound s a NS 3 chelator. 55. A method as set forth in claim 48, wherein said compound is a N 3 S chelator. 56. A method as set forth in claim 28, wherein the compound has a binding affinity for the gastrin releasing peptide receptor that is approximately equal to or greater than that of native bombesin. 57. A method of forming a therapeutic or diagnostic compound comprising the step of reacting a metal complexed with a chelating group with a moiety capable of agonistic binding a gastrin releasing peptide receptor. 58. A method of forming a therapeutic or diagnostic compound comprising a step of reacting a metal with a chelating group already covalently attached to a moiety capable of agonistic binding a gastrin releasing peptide receptor. 59. A method as set forth in claim 57, wherein the moiety capable of binding to a gastrin releasing peptide receptor is a gastrin releasing peptide receptor agonist. 60. A method as set forth in claim 57, wherein the gastrin releasing peptide receptor agonist includes a bombesin agonist binding moiety. 61. A method as set forth in claim 60, wherein the chelated metal is attached to the bombesin agonist binding moiety by a spacer group. 62. A method as set forth in claim 60, wherein the compound has the structure of the formula: X-Y-B wherein X is the group capable of binding a metal; Y is the spacer group or a covalent bond and B is a bombesin binding moiety. 63. A method forth in claim 62, wherein Y is a C,-C I0 hydrocarbon chain. 64. A method as set forth in claim 63, wherein Y is a C 3 -C 9 hydrocarbon chain. 65. A method as set forth in claim 60, wherein Y includes at least one amino acid residue. 66. A method as set forth in claim 65, wherein Y includes a L- Gin residue at the BBN-7 position. 67. A method as set forth in claim 62, wherein the chelating group is attached to the bombesin agonist binding moiety at the N- terminal end of the bombesin agonist binding moiety. 68. A method as set forth in claim 60, wherein the chelating group is attached to the bombesin agonist binding moiety at amino acid residue 8 (D " or L " tφ 8 ) of the bombesin molecule or derivative thereof. 69. A method as set forth in claim 60, wherein the spacer is attached to the bombesin agonist binding moiety at the N-terminal end of the bombesin agonist binding moiety. 70. A method as set forth in claim 60, wherein the spacer is attached to the bombesin agonist binding moiety at amino acid residue 8 (D " or L " tφ 8 ) of the bombesin agonist binding moiety. 71. A method as set forth in claim 57, wherein the metal is a diagnostically or therapeutically useful radioactive metal. 72. A method as set forth in claim 71, wherein the metal is a metallic radioisotope selected form the group including γ and β emitting isotopes. 73. A method as set forth in claim 72, wherein the metallic radioisotope is a radionuclide selected from the group including 186 Re, 188 Re, 99m Tc, 105 Rh, 199 Au, ,53 Sm, 166 Ho and 90 Y. 74. A method as set forth in claim 73, wherein said metallic isotope includes oxides and nitrides thereof. 75. A method as set forth in claim 57, wherein said chelating agent includes a multidentate chelating structure capable of forming a highly stable complex with metals via coordinating atoms. 76. A method as set forth in claim 75, wherein said chelating structure includes the coordinating atoms S, N, O, or P. 77. A method as set forth in claim 75, wherein the chelating structure is a macrocyclic compound including coordinating atoms. 78. A method as set forth in claim 75, wherein said compound is a S 4 chelator. 79. A method as set forth in claim 75, wherein said compound is a N 4 chelator. 80. A method as set forth in claim 75, wherein said compound is a N 2 S 2 chelator. 81. A method as set forth in claim 75, wherein said compound s a NS 3 chelator. 82. A method as set forth in claim 75, wherein said compound is a N 3 S chelator. 83. A method as set forth in claim 57, wherein the compound has a binding affinity for the gastrin releasing peptide receptor that is approximately equal to or greater than that of native bombesin. 84. A method of imaging a tumor site by administering to a subject a diagnostically effective amount of a compound as set forth in claim 1. 85. A method of formulation a pharmaceutical using a kit type method wherein the metal is added to a sealed vial containing a predetermined quantity of a compound described in claim 1 and a reducing agent.

Inventors: HIGGENBOTHAM CHRYS A, HOFFMAN TIMOTHY, NING LI, SIECKMAN GARY, VOLKERT WYNN A, HIGGENBOTHAM, CHRYS, A., HOFFMAN, TIMOTHY, NING, LI, SIECKMAN, GARY, VOLKERT, WYNN, A.
Applicants: CURATOR OF THE UNIVERSITY OF M, HIGGENBOTHAM CHRYS A, HOFFMAN TIMOTHY, NING LI, SIECKMAN GARY, VOLKERT WYNN A, CURATOR OF THE UNIVERSITY OF MISSOURI, HIGGENBOTHAM, CHRYS, A., HOFFMAN, TIMOTHY, NING, LI, SIECKMAN, GARY, VOLKERT, WYNN, A.
Application year: 1998
Main classification: A61K38
IPC codes: A61K38, A61K51, A61P35, C07K7, G01N33