METHODS AND KITS FOR PREPARING RADIONUCLIDE COMPLEXES

Abstract

A method for preparing a complex comprising a radioisotope of gallium for use in radiotherapy or in a medical imaging procedure, said method comprising adding a gallium radioisotope solution obtained directly from a gallium radionuclide generator to a composition comprising a pharmaceutically acceptable buffer and optionally also a pharmaceutically acceptable basic reagent, in amounts sufficient to increase the pH to a level in the range of 3 to 8, wherein the composition further comprises a chelator that is able to chelate radioactive gallium within said pH range and at moderate temperature, said chelator being optionally linked to a biological targeting agent. Kits and compositions for use in the method are also described and claimed.

Claims

1. A method for obtaining a molecular image of a patient, said method comprising: a. having obtained or obtaining radiolabeled DKFZ-PSMA-11 at a temperature of 10 to 30? C. by adding a 0.1 M HCL gallium radioisotope eluate obtained directly from a gallium-68 radionuclide generator, without additional preparation, purification or concentration steps, to a lyophilized or freeze-dried chelator composition comprising: (i) a pharmaceutically acceptable buffer selected from a phosphate and an acetate buffer in an amount sufficient to increase the pH to a level in the range of 3 to 8; and (ii) DKFZ-PSMA-11; b. administering the radiolabeled DKFZ-PSMA-11 directly to a patient in need thereof; and c. obtaining a molecular image of a patient using a molecular imaging technique, wherein the lyophilized or freeze-dried chelator composition does not include agents inhibiting metals other than gallium.

2. The method of claim 1, wherein the pharmaceutically acceptable buffer is in an amount to give 0.1 to 0.5M buffer solution.

3. The method of claim 1, wherein the chelator composition further comprises ascorbic acid or gentisic acid.

4. The method of claim 3, wherein the ascorbic acid or gentisic acid is present in the lyophilized or freeze-dried composition at a weight of from 1-4% w/w.

5. The method of claim 3, wherein the ascorbic acid or gentisic acid is present in the lyophilized or freeze-dried composition at a weight of from 1-2 mg.

6. The method of claim 1, wherein the lyophilized or freeze-dried chelator composition is packaged in a sterile sealed container and the 0.1 M HCl gallium radioisotope eluate obtained directly from the generator is added directly to the sterile sealed container to form an amount of radiolabeled DKFZ-PSMA-11 sufficient for one imaging procedure.

7. The method of claim 1, wherein the molecular imaging technique is selected from positron emission tomography (PET), Single-photon emission computed tomography (SPECT), X-Ray Computed Tomography (CT) and Cerenkov luminescence imaging (CLI).

8. A cold kit for direct radiolabeling of a biological targeting agent with Ga-68, the cold kit comprising: a lyophilized or freeze-dried chelator composition packaged in a single sterile sealed container, wherein the lyophilized or freeze-dried chelator composition does not include agents inhibiting metals other than gallium and comprises: a. a pharmaceutically acceptable buffer selected from a phosphate and an acetate buffer in an amount sufficient to increase the pH to a level in the range of 3 to 8 and b. DKFZ-PSMA-11.

9. The cold kit of claim 8, wherein the pharmaceutically acceptable buffer is in an amount to give 0.1 to 0.5M buffer solution once reconstituted.

10. The cold kit of claim 8, wherein the lyophilized or freeze-dried chelator composition is in an amount sufficient for one or two therapeutic or imaging operations once reconstituted with a 0.1 M HCL gallium radioisotope eluate obtained directly from a gallium-68 radionuclide generator, without additional preparation, purification, or concentration steps.

11. The cold kit of claim 8, wherein the lyophilized or freeze-dried chelator composition further comprises ascorbic acid or gentisic acid.

12. The cold kit of claim 11, wherein the ascorbic acid or gentisic acid is present in the lyophilized or freeze-dried composition at a weight of from 1-4% w/w.

13. The cold kit of claim 11, wherein the ascorbic acid or gentisic acid is present at a weight of from 1-2 mg.

14. The cold kit of claim 8, wherein the lyophilized or freeze-dried chelator composition does not include an additional basic ingredient.

15. The cold kit of claim 8, wherein the kit does not include any other components used for the preparation, purification, or concentration of a gallium radioisotope eluate before or after adding to the lyophilized or freeze-dried chelator composition.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0094] The invention will now be particularly described by way of Example with reference to the accompanying figures in which:

[0095] FIG. 1 is a graph showing the results of a comparison of chelation efficiency of a range of chelators using the method of the invention.

[0096] However, it will be apparent to one skilled in the art that the specific details are not required in order to practice the invention. The following descriptions of specific embodiments of the present invention are presented for purposes of illustration and description. They are not intended to be exhaustive of or to limit the invention to the precise forms disclosed. Many modifications and variations are possible in view of the above teachings. The embodiments are shown and described in order to best explain the principles of the invention and its practical applications, to thereby enable others skilled in the art to best utilize the invention and various embodiments with various modifications as are suited to the particular use contemplated.

EXAMPLE 1

Preparation of .SUP.68.Ga Labelled Reagent

[0097] A range of compositions comprising the chelator CP256 were prepared containing various concentrations of pharmaceutically acceptable buffer (sodium phosphate buffer) and pharmaceutically acceptable basic reagent (sodium hydroxide) as set out in Table 1 below. The mixtures were lyophilised under vacuum overnight.

[0098] An Eckert and Zeigler .sup.68Ga generator was eluted with 0.1M HCl, to produce 5 ml eluents of 300 MBq per elution. Portions (1 ml) of the eluent were added each of the compositions at room temperature.

[0099] The pH of the resultant solutions was measured. The % radiolabelling of the CP256 (THP) was investigated using TLC. The results are also shown in Table 1 below.

TABLE-US-00001 TABLE 1 Reagent(amounts) CP256 NaOH Phosphate buffer Radiolabelling % (nmoles) (mmoles) mmoles) pH TLC 13.5 0.15 0.10 7 >47 13.5 0.10 0.10 7 >74 13.5 0.15 0.25 7 >76 13.5 0.00 0.50 4 >85 13.5 0.10 0.25 7 >89 13.5 0.05 0.25 5-6 >90 13.5 0 0.25 4 >90 13.5 0.05 0.10 5-6 >90 13.5 0 0.10 3-4 >90

[0100] The results show that radiolabelled CP256 was obtained with high levels of efficiency in 2 minutes. The high level of purity in some instances would mean that there is no need to further purify the gallium before administration to patients.

EXAMPLE 2

Preparation of .SUP.68.Ga Labelled Reagent

[0101] The methodology of Example 1 was repeated using a range of formulations comprising 0.13M sodium bicarbonate, 0.1M phosphate buffer (PBS) and a range of CP256 concentrations as listed in the following Table. Highly efficient labelling was achieved in relation to the concentration of the chelator as illustrated in Tables 2 and 2a.

TABLE-US-00002 TABLE 2 CP256(THP) Concentration ?M % Labelling Standard Dev 1000 97.55 1.45 100 95.76 4.84 10 91.52 2.36 1 62.62 7.99 0.1 31.29 4.47 0.001 0.00 1.63

TABLE-US-00003 TABLE 2A CP256(THP) Concentration % Labelling Standard Dev 1 mM 97 0.15 500 ?M 9695.76 1.42 50 ?M 9791.52 0.97 5 ?M 9762.62 0.06 500 nM 981.29 0.14 50 nM 150.00 3.10

EXAMPLE 3

Comparison of Radiolabelling Using Different Chelators

[0102] The method of Example 1 was repeated using a range of different chelators (DOTA, NOTA, TRAP, NOTP, HBED, DFO and THP) at various concentrations. The amounts of phosphate buffer and sodium hydroxide was adjusted to provide a pH of either 4 or 7 on addition of the 0.1M eluate. Solutions were incubated at room temperature for 10 minutes.

[0103] The results at pH 7 are shown in FIG. 1. Acceptable labelling efficiencies in excess of 95% were only found with with THP and DFO. All other chelators did not label >95% at pH 7.0. In addition the concentration of most the other chelators had to be quite high to achieve >90% labelling

EXAMPLE 4

Lyophilised Kit

[0104] A vial comprising a lyophilised reagent mixture, prepared as described above and comprising CP256(THP)(40 ?g) linked to a PSMA targeting agent (30 nmoles), sodium bicarbonate (42 mg), sodium phosphate monobasic anhydrous (8.2 mg) and sodium phosphate dibasic heptahydrate (8.5 mg) is prepared. It could be reconstituted using a 0.1M HCl eluate (5 ml) obtained from an Eckert and Zeigler .sup.68Ga generator to produce a solution of pH 6.5 to 7.0, which may be used in therapy or in molecular imaging.

EXAMPLE 5

Alternative Lyophilised Kit

[0105] A vial comprising a lyophilised reagent mixture as described in Example 4 but also containing from 1 to 2 mg ascorbic acid may also be prepared. This kit also can be reconstituted using a 0.1M HCl eluate (5 ml) obtained from an Eckert and Zeigler .sup.68Ga generator to produce a solution of pH 6.5 to 7.0, which may be used in therapy or in molecular imaging.