DAZA chelators as ligands in liver imaging

Abstract

The invention relates to compounds according to the general formula (I) or a pharmaceutically acceptable salt of an inorganic or organic acid, a hydrate, a stereoisomer or a solvate thereof, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11 and R.sup.12 being selected independently of one another from hydrogen and alkoxy. The compounds of formula (I) as ligands are suitable for the production of radioactively labelled .sup.68Ga, .sup.64Cu, .sup.67Ga, .sup.111In or .sup.99mTc complexes. The invention further relates to a method for producing the compounds of formula (I) and the radioactively labelled complexes and to the use of the radioactively labelled complexes in imaging methods, such as PET/CT, in particular of the liver.

Claims

1. A compound of the general formula I ##STR00008## or a pharmaceutically acceptable salt of an inorganic or organic acid, a hydrate, a stereoisomer or a solvate thereof, including a radiolabeled complex thereof, where R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11, and R.sup.12 are independently selected from hydrogen and alkoxy one or the substituents R.sup.1, R.sup.2, R.sup.3, and R.sup.4 is alkoxy and the other three substituents are hydrogen; and one of the substituents R.sup.5, R.sup.6, R.sup.7, and R.sup.8 is alkoxy and the other three substituents are hydrogen; and one of the substituents R.sup.9, R.sup.10, R.sup.11, and R.sup.12 is alkoxy and the other three substituents are hydrogen.

2. The compound as claimed in claim 1, wherein the radiolabeled complex consists of a compound of the formula I and a radioisotope selected from the group consisting of .sup.68Ga, .sup.64Cu, .sup.67Ga, 111In, and .sup.99mTc, or is a complex corresponding to the general formula II: ##STR00009## or a pharmaceutically acceptable salt of an inorganic or organic acid, a hydrate, a stereoisomer or a solvate thereof, where R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11, and R.sup.12 are as defined in claim 1 and where X is selected from .sup.68Ga, .sup.67Ga, and .sup.111In.

3. The compound as claimed in claim 1, where R.sup.1 is alkoxy and R.sup.2, R.sup.3, and R.sup.4 are hydrogen; and R.sup.5 is alkoxy and R.sup.6, R.sup.7, and R.sup.8 are hydrogen; and R.sup.9 is alkoxy and R.sup.10, R.sup.11, and R.sup.12 are hydrogen; or R.sup.2 is alkoxy and R.sup.1, R.sup.3, and R.sup.4 are hydrogen; and R.sup.6 is alkoxy and R.sup.5, R.sup.7, and R.sup.8 are hydrogen; and R.sup.10 is alkoxy and R.sup.9, R.sup.11, and R.sup.12 are hydrogen; or R.sup.3 is alkoxy and R.sup.1, R.sup.2, and R.sup.4 are hydrogen; and R.sup.7 is alkoxy and R.sup.5, R.sup.6, and R.sup.8 are hydrogen; and R.sup.11 is alkoxy and R.sup.9, R.sup.10, and R.sup.12 are hydrogen; or R.sup.4 is alkoxy and R.sup.1, R.sup.2, and R.sup.3 are hydrogen; and R.sup.8 is alkoxy and R.sup.5, R.sup.6, and R.sup.7 are hydrogen; and R.sup.12 is alkoxy and R.sup.9, R.sup.10, and R.sup.11 are hydrogen.

4. The compound as claimed in claim 1, where R.sup.2 is alkoxy and R.sup.1, R.sup.3, and R.sup.4 are hydrogen; and R.sup.6 is alkoxy and R.sup.5, R.sup.7, and R.sup.8 are hydrogen; and R.sup.10 is alkoxy and R.sup.9, R.sup.11, and R.sup.12 are hydrogen.

5. The compound as claimed in claim 4, where R.sup.2, R.sup.6, and R.sup.10 are independently —O—C.sub.1-12 alkyl and where the alkyl radical may be unbranched or branched.

6. The compound as claimed in claim 5, where R.sup.2, R.sup.6, and R.sup.10 are independently selected from methoxy, ethoxy, propoxy, butoxy, pentoxy, heptoxy, hexoxy and octoxy.

7. The compound as claimed in claim 1, where R.sup.2, R.sup.6, and R.sup.10 are ethoxy.

8. The compound as claimed in claim 1, where R.sup.2, R.sup.6, and R.sup.10 are methoxy.

9. The compound as claimed in claim 1, wherein the compound is selected from tris-N,N′,N″(4-ethoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine and tris-N,N′,N″(4-methoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine.

10. The compound as claimed in claim 2, wherein the compound is selected from .sup.68Ga[tris-N,N′,N″(4-ethoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine], .sup.68Ga[tris-N,N′,N″(4-methoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine], .sup.64Cu[tris-N,N′,N″(4-ethoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine], .sup.64Cu[tris-N,N′,N″(4-methoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine], .sup.67Ga[tris-N,N′,N″(4-ethoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine], .sup.67Ga[tris-N,N′,N″(4-methoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine], .sup.111In[tris-N,N′,N″(4-ethoxy-2-hydroxy-benzyl)-1,4-diazepan-6-amine], .sup.111In[tris-N,N′,N″(4-methoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine], .sup.99mTc[tris-N,N′,N″(4-ethoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine], .sup.99mTc[tris-N,N′,N″(4-methoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine], .sup.68Ga[tris-N,N′,N″(3-ethoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine], .sup.68Ga[tris-N,N′,N″(5-ethoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine], .sup.68Ga[tris-N,N′,N″(6-ethoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine], .sup.68Ga[tris-N,N′,N″(3-methoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine], .sup.68Ga[tris-N,N′,N″(5-methoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine], .sup.68Ga[tris-N,N′,N″(6-methoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine], .sup.64Cu[tris-N,N′,N″(3-ethoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine], .sup.64Cu[tris-N,N′,N″(5-ethoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine], .sup.64Cu[tris-N,N′,N″(6-ethoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine], .sup.64Cu[tris-N,N′,N″(3-methoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine], .sup.64Cu[tris-N,N′,N″(5-methoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine], .sup.64Cu[tris-N,N′,N″(6-methoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine], .sup.67Ga[tris-N,N′,N″(3 -ethoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine], .sup.67Ga[tris-N,N′,N″(5-ethoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine], .sup.67Ga[tris-N,N′,N″(6-ethoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine], .sup.67Ga[tris-N,N′,N″(3-methoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine], .sup.67Ga[tris-N,N′,N″(5-methoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine], .sup.67Ga[tris-N,N′,N″(6-methoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine], .sup.111In[tris-N,N′,N″(3-ethoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine], .sup.111In[tris-N,N′,N″(5-ethoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine], .sup.111In[tris-N,N′,N″(6-ethoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine], .sup.111In[tris-N,N′,N″(3-methoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine], .sup.111In[tris-N,N′,N″(5-methoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine], .sup.111In[tris-N,N′,N″(6-methoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine], .sup.99mTc[tris-N,N′,N″(3-ethoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine], .sup.99mTc[tris-N,N′,N″(5-ethoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine], .sup.99mTc[tris-N,N′,N″(6-ethoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine], .sup.99mTc[tris-N,N′,N″(3-methoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine], .sup.99mTc[tris-N,N′,N″(5-methoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine], and .sup.99mTc[tris-N,N′,N″(6-methoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine].

11. The compound as claimed in claim 2, wherein the compound is selected from .sup.68Ga[tris-N,N′,N″(4-ethoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine], .sup.68Ga[tris-N,N′,N″(4-methoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine], .sup.64Cu[tris-N,N′,N″(4-ethoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine], and .sup.64Cu[tris-N,N′,N″(4-methoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine].

12. A pharmaceutical or radiopharmaceutical composition comprising a compound of the formula I or of the formula II as claimed in claim 2 and one or more pharmaceutically acceptable diluents or vehicles.

13. The pharmaceutical or radiopharmaceutical composition as claimed in claim 12, comprising PBS-buffered saline.

14. A kit for preparing a radiopharmaceutical preparation, wherein the kit comprises a sealed ampoule containing a predetermined amount of a compound of the formula I or of the compound of the formula II and optionally instructions for using the components of the kit, wherein formula I is: ##STR00010## where R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11, and R.sup.12 are independently selected from hydrogen and alkoxy, and formula II is: ##STR00011## where X is selected from .sup.68Ga, .sup.67Ga, and .sup.111In, wherein one of the substituents R.sup.1, R.sup.2, R.sup.3, and R.sup.4 is alkoxv and the other three substituents are hydrogen: and one of the substituents R.sup.5, R.sup.6, R.sup.7, and R.sup.8 is alkoxy and the other three substituents are hydrogen: and one of the substituents R.sup.9, R.sup.10, R.sup.11, and R.sup.12 is alkoxv and the other three substituents are hydrogen.

15. A method for preparing a compound of the general formula I as claimed in claim 1, comprising the steps of a) synthesizing a compound of the formula III ##STR00012## where R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are as defined in claim 1; through reaction of a compound of the formula IV ##STR00013## where R.sup.9, R.sup.10, R.sup.11, and R.sup.12 are as defined in claim 1, with a compound of the formula (V): ##STR00014## in the presence of a suitable solvent, such as methanol; and b) reacting the compound of the formula III under reducing conditions with a suitable reducing agent in the presence of a suitable solvent.

16. A method for preparing a compound of the general formula II as claimed in claim 2 comprising treating a compound of the formula I with a .sup.68Ga-containing solution at a pH of 5.0 or lower or with a .sup.64Cu-containing-solution at a pH of 4.0 or higher.

17. The method as claimed in claim 16, wherein the method is carried out at 50° C. or higher.

18. A method for obtaining an image of the liver of an animal or human, wherein the method comprises the following steps: (a) administering to an animal or human a pharmaceutical composition comprising a compound of the formula II as claimed in claim 2, (b) carrying out a PET or a PET/CT scan of the treated animal or human; (c) detecting a measurable emission signal due to the compound of the formula II from the animal or human concerned; and (d) generating an image from the detectable signal, thereby obtaining an image of the liver of the animal or human.

19. The compound of the formula II as claimed in claim 2, wherein the compound accumulates selectively in the liver.

20. The pharmaceutical composition as claimed in claim 12, wherein the composition has an activity of at least 50 MBq.

21. The pharmaceutical composition as claimed in claim 12, wherein the composition has a stability of at least 98% for at least 4 hours in human serum and PBS-buffered saline.

Description

EXAMPLE EMBODIMENTS

(1) 1. Synthesis Description

(2) The compounds of the formula I are synthesized as shown in scheme 1.

(3) ##STR00007##

(4) Synthesis of Precursors/Synthesis of 1

(5) 1,4-Diazepan-6-amine (65 mg, 0.57 mmol) and 4-methoxy-2-hydroxybenzaldehyde (172 mg, 1.13 mmol) in 15 ml methanol were mixed in a round-bottomed flask and the resulting yellow suspension was stirred for one hour at RT. The solid was filtered, washed with methanol, and dried under reduced pressure (205 mg, 0.54 mmol, 94%).

(6) .sup.1H-NMR (400.1 MHz, CDCl.sub.3): δ=13.17 (s, broad, 1H), 11.85 (s, broad, 1H), 8.28 (s, 2H), 7.26-7.23 (m, 1H), 7.12 (d, .sup.3J.sub.H,H=8.4 Hz, 1H), 6.45-6.36 (m, HH), 5.21 (s, 1H), 3.81 (s, 3H), 3.76 (s, 3H), 3.71-3.64 (m, 1H), 3.37-2.90 (m, 8H).

(7) .sup.13C-NMR (100.6 MHz, CDCl.sub.3): δ=165.0, 163.7, 163.5, 161.2, 158.5, 132.7, 128.0, 112.5, 106.9, 105.5, 101.8, 101.2, 87.4, 60.6, 59.1, 55.6, 55.3, 50.6.

(8) MS (ESI pos., CH.sub.3OH): m/z=383 ([M].sup.+, 100%).

(9) EA [%] (C.sub.21H.sub.25N.sub.3O.sub.4): C 65.46 (65.78), H 6.72 (6.57), N 11.07 (10.96).

(10) Synthesis of Precursors/Synthesis of 2

(11) 1,4-Diazepan-6-amine (30 mg, 0.26 mmol) and 4-ethoxy-2-hydroxybenzaldehyde (86 mg, 0.52 mmol) in 10 ml methanol were mixed in a round-bottomed flask and the resulting yellow suspension was stirred for one hour at RT. The solid was filtered, washed with methanol, and dried under reduced pressure (100 mg, 0.24 mmol, 94%).

(12) .sup.1H-NMR (400.1 MHz, CDCl.sub.3): δ=13.16 (s, 1H), 8.27 (s, 2H), 7.24-7.22 (m, 2H), 7.12-7.09 (m, 2H), 6.45-6.41 (m, 2H), 6.38-6.35 (m, 4H), 5.60 (s), 5.21 (s, 1H), 4.07-3.96 (m, 4H), 3.72-3.64 (m, 1H), 3.49-2.90 (m, 8H), 1.43-1.36 (m, 6H).

(13) .sup.13C-NMR (62.9 MHz, CDCl.sub.3): δ=165.0, 163.4, 163.0, 160.5, 158.5, 132.7, 128.0, 112.3, 107.4, 106.1, 102.3, 101.6, 87.4, 63.8, 63.5, 60.6, 59.1, 50.6, 15.0, 14.8.

(14) MS (ESI pos., CH.sub.3OH): m/z=434 ([M+Na].sup.+, 100%), 412 ([M+H].sup.+, 45%).

(15) EA [%] (C.sub.23H.sub.29N.sub.3O.sub.4): C 66.90 (67.13), H 7.13 (7.10), N 10.26 (10.21).

(16) Synthesis of the Ligand TMeOHB-DAZA

(17) To a solution of 1 (200 mg, 0.52 mmol) in 10 ml of a 1:1 mixture of methanol and chloroform was added 71 mg (1.89 mmol) of NaBH4 in several portions, whereupon the solution decolorized. The reaction solution was stirred for one hour. The solvent was then removed under reduced pressure and the residue resuspended in methanol. The solid was filtered, washed with methanol, and then dried under reduced pressure (163 mg, 0.31 mmol, 60%).

(18) .sup.1H-NMR (400.1 MHz, CDCl.sub.3): δ=10.45 (s, broad, 1H), 6.88 (d, .sup.3J.sub.H,H=8.1 Hz, 2H), 6.52 (d, .sup.3J.sub.H,H=8.4 Hz, 1H), 6.41-6.35 (m, 5H), 6.27 (dd, .sup.3J.sub.H,H=8.3 Hz, .sup.2J.sub.H,H=2.5 Hz, 1H), 3.82 (d, .sup.2J.sub.H,H=13.4 Hz, 2H), 3.75 (s, 6H), 3.74 (s, 3H), 3.67 (d, .sup.2J.sub.H,H=13.4 Hz, 2H), 3.37 (s, 2H), 2.98-2.72 (m, 9H).

(19) .sup.13C-NMR (100.6 MHz, CDCl.sub.3): δ=161.1, 160.6, 159.2, 158.7, 129.7, 129.2, 114.4, 114.0, 105.9, 105.2, 102.1, 102.0, 62.5, 58.3, 57.9, 55.4, 54.7, 51.0, 49.4.

(20) MS (ESI pos., CH.sub.3OH): m/z=546 ([M+Na].sup.+, 45%), 524 ([M+H].sup.+, 100%).

(21) EA [%] (C.sub.32H.sub.45N.sub.3O.sub.7.0.5MeOH): C 65.58 (65.66), H 7.07 (7.28), N 7.89 (7.79).

(22) Synthesis of the Ligand TEOHB-DAZA

(23) To a suspension of 2 (120 mg, 0.29 mmol) in 10 ml of methanol was added 22 mg (0.58 mmol) of NaBH.sub.4 in several portions, whereupon the yellow suspension decolorized within 10 minutes. The resulting solution was stirred for one hour and the solvent was then concentrated to 5 ml. A white solid precipitated out of the methanolic solution overnight, which was filtered, washed with methanol and then dried under reduced pressure (85 mg, 0.15 mmol, 52%).

(24) .sup.1H-NMR (400.1 MHz, CDCl.sub.3): δ=6.86 (d, .sup.3J.sub.H,H=8.1 Hz, 2H), 6.51 (d, .sup.3J.sub.H,H=8.3 Hz, 1H), 6.40-6.33 (m, 5H), 6.25 (dd, .sup.3J.sub.H,H=8.3 Hz, .sup.2J.sub.H,H=2.5 Hz, 1H), 3.96 (q, .sup.3J.sub.H,H=7.0 Hz, 6H), 3.82 (d, .sup.2J.sub.H,H=13.4 Hz, 2H), 3.66 (d, .sup.2J.sub.H,H=13.4 Hz, 2H), 3.35 (s, 2H), 2.98-2.71 (m, 9H), 1.41-1.36 (m, 6H).

(25) .sup.13C-NMR (100.6 MHz, CDCl.sub.3): δ=160.4, 159.9, 159.2, 158.6, 129.7, 129.2, 114.3, 113.9, 106.4, 105.6, 102.6, 102.6, 63.5, 63.4, 62.5, 58.3, 57.9, 54.6, 49.4, 15.0.

(26) MS (ESI pos., CH.sub.3OH): m/z=588 ([M+Na].sup.+, 100%), 566 ([M+H].sup.+, 62%), 438 ([M-(CH.sub.2—C.sub.6H.sub.4O—OC.sub.2H.sub.5)+Na].sup.+, 25%), 416 ([M-(CH.sub.2—C.sub.6H.sub.4O—OC.sub.2H.sub.5)+H].sup.+, 46%).

(27) EA [%] (C.sub.32H.sub.45N.sub.3O.sub.7.H.sub.2O): C 65.49 (65.84), H 7.43 (7.77), N 7.27 (7.20).

(28) Radiolabeling of .sup.68Ga

(29) The cationically purified .sup.68Ga eluate (approx. 1600 MBq) from a .sup.68Ge/.sup.68Ga generator (TiO.sub.2, eluted with 0.6 M hydrochloric acid) was treated with 70 μL of a solution of TMeOHB-DAZA or TEOHB-DAZA (1 mg/ml in Ultrapur® water)/HCl (1 M)/ethanol, 3:1:1) and 2 ml of acetate buffer. The solution with a pH of 3.8-4.0 was heated at 100° C. for 5 minutes. The solution was then loaded onto a preconditioned C8 reversed-phase cartridge (SepPak®, C8 Plus), washed with 2 ml of water (water for injection), and the .sup.68Ga tracer eluted with 1 ml of ethanol (50%). The radiochemical yield was 65-80% (decay corrected). The sample was diluted with PBS (10 ml). The radiochemical purity was determined by radio-TLC and radio-HPLC and was ≥99.6%. The activities were determined in a calibrated activimeter.

(30) Radiolabeling of X (.sup.64Cu, .sup.67Ga, .sup.111In, .sup.99mTc)

(31) An aqueous solution of a compound I with addition of suitable additives or excipients such as buffers, reducing agents (e.g. SnCl.sub.2), stabilizers, emulsifiers etc. and having a pH in a range of 2-12 is treated with an aqueous solution of radiometal X (.sup.64Cu, .sup.67Ga, .sup.111In, .sup.99mTc) having an activity of 1 MBq-100 GBq. The labeling is optionally carried out by heating to a temperature of up to 100° C. for 1 minute to 12 hours. The solution is then purified, concentrated, buffered or diluted so as to have a composition suitable for i.v. administration.

(32) 2. Administration in Ostrich Egg and PET/CT Examination

(33) To carry out an intravascular injection in an embryonic egg, it is first necessary to find an amniotic blood vessel. This is done using a light-intensive Schier lamp (Tempo No. 119, Brecker Ltd. & Co. KG, Ruethen, Germany or Powerlux Eggtester 4.5 VDC, Lyon Technologies Inc., Chula Vista, Calif., USA), with which the egg is illuminated through the eggshell in similar manner to a diaphanoscopy. After locating a large-caliber vessel, an approximately 2.5×5 cm rectangular piece is machined from the approximately 2 mm thick egg shell (Dremel® 3000, Dremel Europe-Bosch Powertools B.V., Breda, the Netherlands). Particular care must be taken to maintain the intactness of the inner membrane of the eggshell, which corresponds to the chorioallantoic membrane (CAM).

(34) After removing the eggshell lid—again using the Schier lamp—the yolk vessel is punctured with a narrow 27G cannula and this is fixed to the eggshell with adhesive strips. The access thus created now allows both CT contrast media and radiopharmaceuticals to be injected via a short length of plastic tubing (Smiths Medical™ 800/100/100 Smiths, Smiths Medical International Ltd, Ashford, Great Britain). To ensure this does not become occluded by blood flowing back and coagulating, it is flushed with heparin.

(35) The tracers .sup.68Ga[TMeOHB-DAZA] and .sup.68Ga[TEOHB-DAZA] produced according to the described method were in each case injected in PBS solution through the access (approx. 10 MBq each, in 0.3-0.8 ml) and this was then immediately rinsed with 1 ml of isotonic saline (0.9%). The administration was carried out in list mode at the start time of the PET imaging procedure.

Summary of the Results of the Example Embodiments

(36) The compounds of the formula I, TEOHB-DAZA and TMeOHB-DAZA, represent ligands that are suitable for labeling with .sup.68Ga and .sup.64Cu. Unlike with the known ligands EOB-DTPA and EHIDA, the .sup.68Ga complexes show no demetalation or decomposition in vivo. The ligands are stable and can be stored as precursors for labeling with .sup.68Ga or .sup.64Cu. Because of the small amounts of substance administered, no adverse toxicological effects are to be expected. The labeling of .sup.68Ga or .sup.64Cu for the synthesis of the complex is carried out according to standard radiopharmaceutical methods. The administration of .sup.68Ga-[TEOHB-DAZA] showed almost exclusive accumulation in the liver in the embryonated ostrich egg (in vivo in the incubated egg). A further advantage is the easy obtainability of the ligands TEOHB-DAZA and TMeOHB-DAZA starting from DAZA via an efficient one-pot synthesis in which only NaBH.sub.4 as reducing agent is used.

REFERENCES

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