Labelled adrenomedullin derivatives and their use for imaging and therapy.

Abstract

The present invention relates to an adrenomedullin derivative including an adrenomedullin peptide, or a fragment thereof chelated or otherwise bound to at least one active agent. Examples of active agents include a paramagnetic element, a radioactive element and a fibrinolytic agent, among others. Paramagnetic agents have a distribution that is relatively easily shown through Magnetic Resonance Imaging (MRI). Radioactive agents have applications in imaging and delivery of radiations, depending on the specific element included in the active agent. Delivery of fibrinolytic agents mainly to a specific organ, such as for example to the lungs, allows to substantially improve the specificity and efficacy of thrombolytic therapy by allowing local delivery of the fibrinolytic agent, thereby reducing the risks of major bleeding in the therapy of the organ. If the organ is the lungs, a non-limiting example of pathology treatable with the fibrinolytic agent is pulmonary embolus.

What is claimed is: 
     
         1 . A method of determining a disease state in an organ in a mammal, the organ comprising adrenomedullin-receptor-bearing cells, the method comprising:
 a) administering to the mammal a labelled adrenomedullin derivative in an effective amount to achieve binding between the labelled adrenomedullin derivative and the adrenomedullin-receptor-bearing cells;   b) generating an image of the distribution of the labelled adrenomedullin derivative in the organ of the mammal;   c) using the image of step b) to determine a labelling pattern of the adrenomedullin derivative in the organ;   d) comparing the labelling pattern of step c) to a labelling pattern of a non diseased organ; and   e) determining the disease state of the organ at least in part on the comparison of step d).   
     
     
         2 . The method of  claim 1  wherein the organ is a lung. 
     
     
         3 . The method of  claim 2 , wherein the disease is pulmonary embolus and wherein the labelling pattern of step c) indicates that the labelled adrenomedullin derivative is present in a greater concentration in upstream regions of the lung than in downstream regions of the lung. 
     
     
         4 . The method of  claim 3 , wherein detecting the pulmonary embolus includes identifying a labelling pattern in a region of the lung in which the labelled adrenomedullin derivative is present in a lower concentration than in adjacent regions of the lung. 
     
     
         5 . The method of  claim 2 , wherein the disease is pulmonary arterial hypertension. 
     
     
         6 . The method of  claim 5 , wherein determining the presence of pulmonary arterial hypertension includes detecting a reduced uptake of the labelled adrenomedullin derivative as compared to a baseline uptake of the labelled adrenomedullin derivative in the non diseased organ, wherein the reduced uptake indicates pulmonary arterial hypertension. 
     
     
         7 . The method of  claim 1 , wherein the organ is a kidney. 
     
     
         8 . The method of  claim 7 , wherein the disease is kidney damage. 
     
     
         9 . The method of  claim 8 , wherein determining the kidney damage includes identifying a labelling pattern in a region of the kidney in which the labelled adrenomedullin derivative is present in a lower concentration than in adjacent regions of the kidney. 
     
     
         10 . The method of  claim 8 , wherein determining the kidney damage includes detecting a reduced uptake of the labelled adrenomedullin derivative as compared to a baseline uptake of the labelled adrenomedullin derivative in the non diseased organ, wherein the reduced uptake indicates kidney damage. 
     
     
         11 . The method of  claim 1 , wherein the mammal is human. 
     
     
         12 . The method of  claim 1  wherein the labelled adrenomedulin derivative is administered to the mammal at a substantially hemodynamically inactive dose. 
     
     
         13 . The method of  claim 1 , wherein the labelled adrenomedullin derivative is labelled with an active agent, said active agent comprising an element selected from the group consisting of Fe, Ca, Mn, Mg, Cu, and Zn. 
     
     
         14 . The method of  claim 1 , wherein the labelled adrenomedullin derivative is labelled with a radioactive element. 
     
     
         15 . The method of  claim 1 , wherein the labelled adrenomedullin derivative comprises: an adrenomedullin peptide or a fragment thereof bound with a radioactive element, the adrenomedullin peptide being a mammalian adrenomedullin peptide. 
     
     
         16 . The method of  claim 15 , wherein the adrenomedullin peptide comprises an adrenomedullin fragment having the sequence: X1-X2-X3-X4-Thr-Val-Gln-Lys-Leu-Ala-His-Gln-lle-Tyr-Gln-Phe-Thr-Asp-Lys-Asp-Lys-Asp-Asn-Val-Ala-Pro-Arg-Ser-Lys-Ile-Ser-Pro-Gln-Gly-Tyr (SEQ ID NO:3), wherein:
 X1 is absent or is selected from the group consisting of: Tyr-Arg-Gln-Ser-Met-Asn-Asn-Phe-Gln-Gly-Leu-Arg-Ser-Phe-Gly, Ser-Phe-Gly and Gly-Gly-Ala-Gly;   X2 is Cys or HomoCys;   X3 is Arg-Phe-Gly-Thr or a linear or branched PEG moiety having at least two Poly(ethylene glycol) (PEG) subunits; and   X4 is Cys or HomoCys.   
     
     
         17 . The method of  claim 16 , wherein wherein X3 is a linear PEG moiety having 2 or 4 PEG subunits. 
     
     
         18 . The method of  claim 16 , wherein X1 is Gly-Gly-dAla-Gly. 
     
     
         19 . The method of  claim 16 , wherein X1 is Gly-Gly-Ala-Gly, X2 is Cys, X3 is a linear moiety having 2 or 4 PEG subunits, and X4 is Cys. 
     
     
         20 . The method of  claim 16 , wherein the adrenomedullin peptide is in a cyclic form. 
     
     
         21 . The method of  claim 16 , wherein the radioactive element is bound directly to an amino acid of the adrenomedullin peptide. 
     
     
         22 . The method of  claim 16 , wherein the radioactive element is chelated to the adrenomedullin peptide. 
     
     
         23 . The method of  claim 22 , wherein said labelled adrenomedulin derivative is chelated to said radioactive agent through diethylenetriaminepentaacetic acid (DTPA). 
     
     
         24 . The method of  claim 16 , wherein the radioactive element is  99m Tc. 
     
     
         25 . The method of  claim 16 , wherein the adrenomedullin peptide is in a linear form. 
     
     
         26 . The method of  claim 16 , wherein the radioactive element is bound directly to a cysteine amino acid of the adrenomedullin peptide. 
     
     
         27 . The method of  claim 14 , wherein the labelled adrenomedulin derivative is administered to the mammal by injection comprising from about 0.5 mCi to about 1000 mCi of labelled adrenomedulin derivative. 
     
     
         28 . The method of  claim 1 , wherein the labelled adrenomedullin derivative is dissolved into a buffer solution, administering the labelled adrenomedullin derivative to the mammal comprising injecting into the bloodstream of the mammal the labelled adrenomedullin derivative dissolved into the buffer solution.