68GA- AND 64CU -NODAGA-E[C(RGDYK)]2 FOR USE AS PET TRACERS IN THE IMAGING OF ANGIOGENESIS IN HUMANS

Abstract

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.

Claims

1. A method of imaging tissue in a human for detecting progression of angiogenesis, said method comprising contacting with or administering to a tissue a compound of formula I, ##STR00005## and imaging the tissue with an imaging system.

2. The method of claim 1, wherein imaging includes imaging cancer in the tissue.

3. The method of claim 1, wherein the imaging system is a PET imaging system.

4. A method of diagnosing the presence of one or more angiogenesis related diseases comprising: contacting or administering to a tissue a compound of formula I, ##STR00006## and imaging the tissue with an imaging system, wherein the location of the compound corresponds to the location of the angiogenesis related diseases.

5. The method of claim 4, wherein imaging includes imaging cancer in the tissue.

6. The method of claim 4, wherein the imaging system is a PET imaging system.

7. The method of claim 4, wherein the imaging includes imaging of liver tumor or metastasis, neuroendocrine tumors, breast cancer, or lymph node metastases.

8. A method of imaging tissue in a human for detecting progression of angiogenesis, said method comprising contacting with or administering to a tissue [64Cu]NODAGA-E[c(RGDyK)]2, and imaging the tissue with an imaging system.

9. The method of claim 8, wherein imaging includes imaging cancer in the tissue.

10. The method of claim 8, wherein the imaging system is a PET imaging system.

11. A method of diagnosing the presence of one or more angiogenesis related diseases comprising contacting or administering to a tissue [64Cu]NODAGA-E[c(RGDyK)]2 and imaging the tissue with an imaging system, wherein the location of the compound corresponds to the location of the angiogenesis related diseases.

12. The method of claim 11, wherein imaging includes imaging cancer in the tissue.

13. The method of claim 11 wherein the imaging system is a PET imaging system.

14. The method of claim 8, wherein the imaging includes imaging of liver tumor or metastasis, neuroendocrine tumors, breast cancer, or lymph node metastases.

15. A method of imaging angiogenic response in tissue of a human heart, said method comprising contacting with or administering to a tissue a compound of formula I, ##STR00007## and imaging the tissue with an imaging system.

16. The method according to claim 15, wherein the angiogenic response is imaged after myocardial infarction or in response to angiogenic therapy.

17. A method of imaging angiogenic response in tissue of a human heart, said method comprising contacting with or administering to a tissue [64Cu]NODAGA-E[c(RGDyK)]2 and imaging the tissue with an imaging system.

18. The method according to claim 17, wherein the angiogenic response is imaged after myocardial infarction or in response to angiogenic therapy.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0024] FIG. 1 shows angiognenesis PET scan of primary neuroendocrine tumor in the intestine. The tracer used was ([.sup.68Ga]NODAGA-E[c(RGDyK)].sub.2.

[0025] FIG. 2 shows angiogenesis PET scan of liver metastases from a neuroendocrine tumor. Please note the high uptake anteriorly in the metastasis. The tracer used was ([.sup.68Ga]NODAGA-E[c(RGDyK)].sub.2.

[0026] FIG. 3 shows angiogenesis PET scan of primary breast cancer.

[0027] FIG. 4 shows angiogenesis PET scan of lymph node metastasis from breast cancer.

[0028] FIG. 5 shows angiogenesis in a human myocardial infarction.

DETAILED DESCRIPTION OF THE INVENTION

[0029] As the active substance ([.sup.6Ga]NODAGA-E[c(RGDyK)].sub.2) is never obtained in its isolated form, but is instead automatically formulated in the final product. Data on manufacture, characterisation and analysis of the active substance is essentially the same as for the drug product and this can, therefore, be found in the following. [.sup.68Ga]NODAGA-E[c(RGDyK)].sub.2 is produced by labelling NODAGA-E[c(RGDyK)].sub.2 acetate with GaCl.sub.3 in the presence of a 1.4 M sodium acetate buffer containing ethanol as a scavenger (stabilizer against radiolysis). Similarly the corresponding 64Cu conjugate can be produced by a 64Cu salt.

##STR00004##

[0030] The product is formulated as an isotonic sterile injection solution. The labelled product is eluted from a solid phase extraction cartridge (C18) with sterile 50% ethanol solution, then through a vented 0.22 m sterile filter into an empty sterile 10 m vial. The labelled product is formulated with a sterile saline solution, which is passed through the C18 cartridge, then through the 0.22 m sterile filter into the sterile 10 ml vial.

[0031] Radiosynthesis is carried out on a ModularLab PharmTracer chemistry system, and the synthesis has been optimized regarding buffer pH (1.4 M NaOAc buffer, pH 4.5), reaction temperature (60 C.) and time (300 sec) with respect to radiochemical yield. The reaction mixture is purified with a C-18 SepPak cartridge to ensure high radiochemical purity. Any free gallium ions will pass through the cartridge, whilst the labelled product is retained and subsequently eluted with 50% aqueous ethanol.

[0032] A phase I trial has successfully been conducted with the new radio tracer 68Ga-NODAGA-E[c(RGDyK)]2 for PET imaging of angiogenesis. The tracer identifies the tumors in humans with a high level of angiogenesis. Furthermore, the tracer has shown to be useful in early response assessment to anti-angiogenic treatment. In addition, ongoing phase II studies have demonstrated uptake in various cancer types as well as in myocardial infarction in patients.

[0033] This human study has also confirmed sufficient safety, biodistribution and dosimetry in repeated PET imaging (10 minutes, 1 hour and 2 hours post injection).

[0034] As appears from FIGS. 1 and 3 that the tracer clearly detects primary tumors of different types, e.g. neuroendocrine tumors and breast cancer.

[0035] In FIGS. 2 and 4 the scans give surprising well-resolved pictures of angiogenesis associated with liver metastases originating from a neuroendocrine tumor and a lymph node metastasis form a breast cancer.

[0036] In FIG. 5 there is shown Imaging of the angiogenic (arrow) response in a days old myocardial infarction in a human patient clearly demonstrating that in this particular patient induction of angiogenesis was seen. This may be used e.g. for risk stratification, selection of therapy or monitoring of therapy.