The present invention provides bi-terminal PEGylated peptide conjugates that target an integrin such as .sub.v.sub.6 integrin. In particular embodiments, the peptide conjugates of the present invention further comprise a biological agent such as an imaging agent or a therapeutic agent, e.g., covalently attached to one of the PEG moieties. The peptide conjugates of the present invention are particularly useful for imaging a tumor, organ, or tissue and for treating integrin-mediated diseases and disorders such as cancer, inflammatory diseases, autoimmune diseases, chronic fibrosis, chronic obstructive pulmonary disease (COPD), lung emphysema, and chronic wounding skin disease. Compositions and kits containing the peptide conjugates of the present invention find utility in a wide range of applications including, e.g., in vivo imaging and immunotherapy.

A process for the preparation of a radionuclide imaging agent includes providing an imaging agent including a chelated place-holder metal; loading the imaging agent onto an acid stable stationary phase; replacing the chelated place-holder metal of the imaging agent loaded on the stationary phase with a replacement radioactive metal under mild reaction conditions; and eluting the imaging agent including the chelated replacement radioactive metal from the stationary phase to provide a radionuclide imaging agent suitable for positron emission tomography (PET) or single-photon emission computed tomography (SPECT). The imaging agent can include a targeting agent that is directly conjugated to the imaging agent or by means of a linker. The process may also apply to other metals that are non-radioactive but used as diluent metals or other metals that are strongly bound to DOTA.

The present invention provides a targeted prodrug enzyme fusion carrier comprising a targeted molecule and a prodrug enzyme. The targeted prodrug enzyme fusion carrier can effectively identify and bind to tumor cells and tumor-induced tumor angiogenesis. The targeted prodrug enzyme fusion carrier also has a targeted prodrug enzyme fusion protein and a theranostic system utilizing the method of in vivo nuclear medicine for the clinical diagnosis and treatment of individual patients with tumors.

The present invention provides a multivalent compound for targeted molecular imaging and/or targeted drug delivery, wherein two components or targeting molecules each interacts with one or more biomarkers on a cell. The present invention further provides a multifunctional chelator to combine the targeting molecules. The present invention also provides an in vitro high-throughput screening assay to determine the length of the spacer molecules. The present invention also relates to compounds/probes, kits and methods for use in targeted molecular imaging and/or targeted drug delivery.

Engineered peptides that bind with high affinity (low equilibrium dissociation constant (Kd)) to the cell surface receptors of fibronectin (.sub.5.sub.1) or vitronectin (.sub.v.sub.3 and .sub.v.sub.5 integrins) are disclosed as useful as imaging tissue. These peptides are based on a molecular scaffold into which a subsequence containing the RGD integrin-binding motif has been inserted. The subsequence (RGD mimic) comprises about 9-13 amino acids, and the RGD contained within the subsequence can be flanked by a variety of amino acids, the sequence of which was determined by sequential rounds of selection (in vitro evolution). The molecular scaffold is preferably based on a knottin, e.g., EETI (Trypsin inhibitor 2 (Trypsin inhibitor II) (EETI-II) [Ecballium elaterium (Jumping cucumber)], AgRP (Agouti-related protein), and Agatoxin IVB, which peptides have a rigidly defined three-dimensional conformation. It is demonstrated that EETI tolerates mutations in other loops and that the present peptides may be used as imaging agents.

Compounds comprising R-G-Cysteic Acid (i.e., R-G-NHCH(CH.sub.2SO.sub.3H)COOH or Arg-Gly-NHCH(CH.sub.2SO.sub.3H)COOH) and derivatives thereof, including pharmaceutically acceptable salts, hydrates, stereoisomers, multimers, cyclic forms, linear forms, drug-conjugates, pro-drugs and their derivatives. Also disclosed are methods for making and using such compounds including methods for inhibiting integrins including but not necessarily limited to .sub.5.sub.1-Integrin, .sub.v.sub.3-Integrin and .sub.v.sub.5-Integrin, inhibiting cellular adhesion to RGD binding sites, preventing or treating viral or other microbial infections, inhibiting angiogenesis in tumors, retinal tissue or other tissues or delivering other diagnostic or therapeutic agents to RGD binding sites in human or animal subjects.

The invention relates to ligands and complexes of metal ions with the ligands useful in various applications, including therapeutic and diagnostic applications.

The present invention relates to compounds that are useful as metal ligands and which either contain a molecular recognition moiety or can be bound to a molecular recognition moiety and methods of making these compounds. Once the compounds that contain a molecular recognition moiety are coordinated with a suitable metallic radionuclide, the coordinated compounds are useful as radiopharmaceuticals in the areas of radiotherapy and diagnostic imaging. The invention therefore also relates to methods of diagnosis and therapy utilising the radiolabelled compounds of the invention.

There is provided two angiogenesis clinical PET tracers, namely 68Ga-NODAGA-E[c(RGDyK)]2 and 64Cu-NODAGA-E[c(RGDyK)]2 for imaging of neo-angiogenesis in humans.

The present invention provides a peptide that selectively binds v6 integrin, the peptide having an amino acid sequence comprising the motif X.sub.1B.sub.nRGDLX.sub.2X.sub.3X.sub.4Z.sub.mX.sub.5, wherein X.sub.1 is any D-amino acid, B.sub.n is a sequence of any n amino acids, which may be natural or unnatural, D- or L-, and may be the same or different, wherein n is a number between 1 and 10, X.sub.2 and X.sub.3 are independently selected from any amino acid, X.sub.4 is Leu or Ile, Z.sub.m is a sequence of any m amino acids, which may be natural or unnatural, D- or L-, and may be the same or different, wherein m is a number between 1 and 10, X.sub.5 is any L- or D-amino acid. Also provided are conjugates comprising said peptide, pharmaceutical compositions comprising said peptide or said conjugates, and uses of said peptide, conjugate or composition, for example, in the treatment, imaging and/or diagnosis of an v6-expressing tumour in a mammalian subject.