PARA-AMINOHIPPURIC ACID (PAH) AS A RENAL PROTECTIVE SUBSTANCE

Abstract

The present application discloses para-aminohippuric acid (PAhI) or a pharmaceutically acceptable salt or carboxylic acid derivate thereof for use in a method for the reduction of nephrotoxic side effects of radiolabeled and non-radiolabeled therapeutic and diagnostic compounds in a subject. Also disclosed are pharmaceutical compositions comprising a radiolabeled and/or non-radiolabeled pharmaceutical compound and para-aminohippuric acid (PAH) or a pharmaceutically acceptable salt or carboxylic acid derivate thereof, and a pharmaceutically acceptable excipient, diluent, carrier or a combination thereof. Another subject of the present application is a method for the reduction of nephrotoxic side effects of radiolabeled and non-radiolabeled therapeutic and diagnostic compounds in a subject comprising administering to a subject para-aminohippuric acid (PAH) or a pharmaceutically acceptable salt or carboxylic acid derivate thereof in combination with a radiolabeled or non-radiolabeled therapeutic or diagnostic compound.

Claims

1.-14. (canceled)

15. A pharmaceutical composition comprising a radiolabeled and/or non-radiolabeled pharmaceutical compound and para-aminohippuric acid (PAH) or a pharmaceutically acceptable salt or carboxylic acid derivate thereof, and a pharmaceutically acceptable excipient, diluent, carrier or a combination thereof.

16. The pharmaceutical composition according to claim 15, wherein the composition comprises a radiolabeled pharmaceutical compound which is a radionuclide containing conjugate molecule comprising a carrier molecule, a chelator and a radionuclide.

17. The pharmaceutical composition according to claim 16, wherein the carrier molecule is selected from peptides, peptidomimetics, antibody fragments, antibody mimetics, small molecules, and knottings.

18. The pharmaceutical composition according to claim 17, wherein the carrier molecule is selected from somatostatin analogues, PSMA-inhibitors, gastrin analogues, integrin binding molecules and folate conjugates.

19. The pharmaceutical composition according to claim 18, wherein the carrier molecule is selected from Tyr3-octeotride, Tyr3-octreotate, JR11, PSMA-11, Sargastrin, RGD and folate.

20. The pharmaceutical composition according claim 16, wherein the chelator is selected from DOTA, HBED-CC, NOTA, NODAGA, DOTAGA, DOTAM, TRAP, NOPO, PCTA, DFO, DTPA, DO3AP, DO3AP.sup.PrA, DO3AP.sup.ABn, and HYNIC or derivatives thereof.

21. The pharmaceutical composition according to claim 16, wherein the radionuclide is selected from the group consisting of .sup.94Tc, .sup.99mTc, .sup.90In, .sup.111In, .sup.67Ga, .sup.68Ga, .sup.86Y, .sup.90Y, .sup.177Lu, .sup.161Tb, .sup.186Re, .sup.188Re, .sup.64Cu, .sup.67Cu, .sup.55Co, .sup.57Co, .sup.43Sc, .sup.44Sc, .sup.47Sc, .sup.225Ac, .sup.213Bi, .sup.212Bi, .sup.212Pb, .sup.227Th, .sup.153Sm, .sup.166Ho, .sup.166Dy, .sup.18F and .sup.131I.

22. The pharmaceutical composition according to claim 21, wherein the radionuclide is selected from .sup.177Lu, .sup.225AC and .sup.68Ga.

23. The pharmaceutical composition according to claim 16, wherein the radionuclide containing conjugate molecule is selected from [.sup.177Lu-DOTA.sup.o-Tyr3]-octreotide, .sup.177Lu-DOTA-JA11, .sup.177Lu-DOTA-RGD, .sup.177Lu-DOTA-Sargastrin, .sup.68Ga-HBED-CC-PSMA-11, .sup.177Lu-PSMA I&T and .sup.99mTc-Etarforlatide.

24. The pharmaceutical composition according to claim 15, wherein the composition further comprises a further substance which reduces nephrotoxic side effects of radiolabeled and non-radiolabeled therapeutic and diagnostic compounds.

25. The pharmaceutical composition according to claim 24, wherein the substance reducing nephrotoxic side effects of therapeutic and diagnostic compounds is selected from amino acids, gelatine, Amifostine, albumin-derived peptides, PSMA-binding molecules, such as PMPA, and vitamins.

26. The pharmaceutical composition according to claim 15, wherein the therapeutic or diagnostic compound and PAH are present in the pharmaceutical composition in a ratio of from 1/240000 to 1/8000 (w/w).

27. The pharmaceutical composition according to claim 15, wherein the pharmaceutically acceptable salt of PAH is aminohippurate sodium.

28. A kit comprising: para-aminohippuric acid (PAH) or a pharmaceutically acceptable salt or carboxylic acid derivate thereof in one part of the kit, and a radiolabeled and/or non-radiolabeled therapeutic or diagnostic compound and/or a pharmaceutical composition according to claim 15 in another part of the kit.

29.-30. (canceled)

31. A method for the reduction of nephrotoxic side effects of radiolabeled and non-radiolabeled therapeutic and diagnostic compounds in a subject comprising administering a pharmaceutical composition according to claim 15 to a subject prior, during or after imaging or therapy using a radiolabeled and/or non-radiolabeled compound.

32. A method for the reduction of nephrotoxic side effects of radiolabeled and non-radiolabeled therapeutic and diagnostic compounds in a subject comprising administering to a subject para-aminohippuric acid (PAH) or a pharmaceutically acceptable salt or carboxylic acid derivate thereof in combination with a radiolabeled or non-radiolabeled therapeutic or diagnostic compound, wherein the administration of PAH is prior and/or during and/or after administration of the radiolabeled or non-radiolabeled therapeutic or diagnostic compound.

33. The method according to claim 32, wherein the method is for the reduction of nephrotoxic side effects of radiopharmaceuticals in radio ligand therapy or diagnostic, wherein the radiopharmaceutical is a radionuclide containing conjugate molecule comprising a carrier molecule, a chelator and a radionuclide.

34. The method according to claim 33, wherein the carrier molecule is selected from peptides, peptidomimetics, small molecules, and knottings.

35. The method according to claim 34, wherein the carrier molecule is selected from somatostatin analogues, PSMA-inhibitors, gastrin analogues, integrin binding molecules and folates.

36. The method according to claim 35, wherein the carrier molecule is selected from Tyr3-octeotride, Tyr3-octreotate, JR11, PSMA-11, Sargastrin, RGD and folate.

37. The method according to claim 33, wherein the chelator is selected from DOTA, HBED-CC, NOTA, NODAGA, DOTAGA, DOTAM, TRAP, NOPO, PCTA, DFO, DTPA, DO3AP, DO3AP.sup.PrA, DO3AP.sup.ABn, and HYNIC or derivatives thereof.

38. The method according to claim 33, wherein the radionuclide is selected from the group consisting of .sup.94Tc, .sup.99mTc, .sup.90In, .sup.111In, .sup.67Ga, .sup.68Ga, .sup.86Y, .sup.90Y, .sup.177Lu, .sup.161Tb, .sup.186Re, .sup.188Re, .sup.64Cu, .sup.67Cu, .sup.55Co, .sup.57Co, .sup.43Sc, .sup.44Sc, .sup.47Sc, .sup.225Ac, .sup.213Bi, .sup.212Bi, .sup.212Pb, .sup.227Th, .sup.153Sm, .sup.166Ho, .sup.166Dy, .sup.18F and .sup.131I.

39. The method according to claim 38, wherein the radionuclide is selected from .sup.177Lu, .sup.225AC and .sup.68Ga.

40. The method according to claim 33, wherein the radionuclide containing conjugate molecule is selected from [.sup.177Lu-DOTA.sup.o-Tyr3]-octreotide, .sup.177Lu-DOTA-JA11, .sup.177Lu-DOTA-RGD, .sup.177Lu-DOTA-Sargastrin, .sup.68Ga-HBED-CC-PSMA-11, .sup.177Lu-PSMA I&T and .sup.99mTc-Etarforlatide.

41. The method according to claim 31, wherein para-aminohippuric acid (PAH) or a pharmaceutically acceptable salt or carboxylic acid derivate thereof further comprising administering a further substance which reduces nephrotoxic side effects of radiolabeled and non-radiolabeled therapeutic and diagnostic compounds to the subject.

42. The method according to claim 41, wherein the substance reducing nephrotoxic side effects of radiolabeled and non-radiolabeled therapeutic and diagnostic compounds is selected from amino acids, gelatine, Amifostine, albumin-derived peptides, PSMA-binding molecules, such as PMPA, and vitamins.

43. The method according to claim 31, wherein PAH or a pharmaceutically acceptable salt or carboxylic acid derivate thereof is administered in an amount of 5 mg to 500 mg per kilogram of body weight.

44. The method according to claim 31, wherein the therapeutic and/or diagnostic compound(s) and PAH or a pharmaceutically acceptable salt or carboxylic acid derivate thereof are administered in a ratio of from 1/240000 to 1/8000 (w/w).

45. The method according to claim 31, wherein the pharmaceutically acceptable salt of PAH is aminohippurate sodium.

Description

FIGURES

[0167] FIG. 1 shows the kidney uptake of [.sup.177Lu-DOTA.sup.o-Tyr3]-octreotide with co-infusion of amino acids and PAH over time, wherein 0.9% NaCl is used as control.

[0168] FIG. 2 shows the reduction of [.sup.177Lu-DOTA.sup.o-Tyr3]-octreotide uptake in kidneys compared to baseline (0.9% NaCl infusion) in percent with co-infusion of amino acids and PAH over time.

[0169] FIG. 3 shows the percent injected dose of [.sup.177Lu-DOTA.sup.o-Tyr3]-octreotide in the kidney with co-injection of 0.9% NaCl, Lys/Arg and PAH at an early time point of 0.5 h p.i.

[0170] FIG. 4 shows the percent injected dose of [.sup.177Lu-DOTA.sup.o-Tyr3]-octreotide in the kidney with co-injection of 0.9% NaCl, Lys/Arg and PAH at late time point of 24 h p.i.

[0171] FIG. 5 shows the ex-vivo organ uptake of [.sup.177Lu-DOTA.sup.o-Tyr3]-octreotide 5 min and 60 min p.i. (N=5). PAH significantly reduced the uptake in the kidneys even at early time point. (**P≤0.005, ****P≤0.0005).

[0172] FIG. 6 shows percentage of injected radioactivity present in kidneys at different time points after injection (0.5, 1, 4, 24 h) of different radiolabeled (Lu-177) agents (DOTA-RGD, Affilin, DOTA-Sargastrin, DOTA-JR11) with co-injection of PAH (200 mg/mL) and 0.9% NaCl, respectively.

[0173] FIG. 7 shows percentage of injected radioactivity present in blood at different time points after injection (0.5, 1, 4, 24 h) of different radiolabeled (Lu-177) agents (DOTA-RGD, Affilin, DOTA-Sargastrin, DOTA-JR11) with co-injection of PAH (200 mg/mL) and 0.9% NaCl, respectively.

[0174] FIG. 8 shows percentage of injected radioactivity present in kidneys (upper lane) and blood (lower lane) at different time points after injection (0.1, 0.5, 1, 2, 4 h) of .sup.68Ga-labeled HBED-CC-PSMA-11 with co-injection of PAH (200 mg/mL) and 0.9% NaCl, respectively.

[0175] FIG. 9 graphically shows the results of a biodistribution analysis of .sup.177Lu-DOTATOC given intravenously to mice after intraperitoneal injection of PAH or physiological saline solution.

[0176] FIG. 10 graphically shows the results of a biodistribution analysis of .sup.99mTc-Etarfolatide given intravenously to mice after intraperitoneal injection of PAH or physiological saline solution.

[0177] FIG. 11 shows a comparative bar diagram of three groups of rats injected with .sup.177Lu-PSMA I&T, injected with Saline VE, Probenecid KP2 or PAH KP1 solution, in % of injected radioactivity in the kidneys.

[0178] FIG. 12 shows a comparative bar diagram of three groups of rats injected with .sup.177Lu-PSMA I&T, injected with Saline VE, Probenecid KP2 or PAH KP1 solution, in % of injected radioactivity in the left heart ventricle.

[0179] FIG. 13 shows a comparative bar diagram of three groups of rats injected with .sup.177Lu-PSMA I&T, injected with Saline VE, Probenecid KP2 or PAH KP1 solution, in % of injected radioactivity in the left renal medulla.

[0180] FIG. 14 shows a comparative bar diagram of three groups of rats injected with .sup.177Lu-PSMA I&T, injected with Saline VE, Probenecid KP2 or PAH KP1 solution, in % of injected radioactivity in the renal cortex.

EXAMPLES

[0181] The following data indicate that co-medication with sodium aminohippurate solutions (PAH) have a significant effect in reducing renal retention and uptake of various radiopharmaceuticals, comprising various carrier molecules, various chelators and various radionuclides, respectively, and that PAH administration is much more effective than Lysine and Arginine infusions. Further, it was found that bioavailability of radiopharmaceuticals is enhanced, and the tumor uptake of radiopharmaceuticals is increased by co-medication with PAH.

Experimental Protocols (Examples 1 and 2)

SPECT/CT Experiments:

[0182] Determination of kidney biodistribution by volumes of interest (VOIs) in the three-dimensional radioactive images, acquired in the six groups of 3 animals per kidney protection agent with [177Lu-DOTA.sup.o-Tyr3]-octreotide in healthy Wistar rats by Single Photon Emission Computed Tomography (SPECT). 50 MBq of [177Lu-DOTA.sup.o-Tyr3]-octreotide was co-administered with amino acid solution (L-Arg and L-Lys)—200 mg/mL in water for injection, sodium para-aminohippurate solution—200 mg/mL in water for injection (PAH) and NaCl 0.9% solution as reference. Imaging acquisition was performed after 0.5 h, 1 h, 4 h, 8 h, 24 h p.i.

Ex-Vivo Organ Distribution:

[0183] All animals were pre-injected 10 min before the radiotracer injection with 1.0 mL of NaCl, Arg-Lys or PAH. The injection solutions for the biodistribution were prepared as a mix of 12 μL [.sup.177Lu]Lu-DOTA-TOC, 1.5 mL NaCl or Arg-Lys or PAH.

[0184] The injection solutions for the SPECT animals were prepared as a mix of 80 μL [177Lu]Lu-DOTA-TOC, 1.5 mL NaCl or Arg-Lys or PAH. The animals were injected and sacrificed after 5 min or 60 min. Organs and tissue of interest were harvested and measured for activity. The male Wistar rats had an average body weight of 210±12 g (5 min) and 218±13 g (60 min). The average injected activity was 4.49±0.38 MBq/kg body weight (5 min) and 159±13 MBq/kg body weight (5 min) for the SPECT and 4.19±0.57 MBq/kg body weight (60 min) or 139±8 MBq/kg body weight for the SPECT animals (60 min).

[0185] For statistical analysis Microsoft Excel 2010 and Graphpad Prism 6.05 were employed. Data are presented as median and [25% and 75% percentile] and mean and standard deviation (SD) or standard error of mean (SEM). For comparison, ordinary one way ANOVA and Tukey's multiple comparisons test, two-sample two-tailed t-test were employed. Significance was accepted with P<0.05.

Example 1: Kidneys Uptake of [.SUP.177.Lu-DOTA.SUP.o.-Tyr3]-octreotide

[0186] The kidneys uptake of [.sup.177Lu-DOTA.sup.o-Tyr3]-octreotide was determined by quantitative small animal SPECT in rats with co-infusion of 0.9% NaCl (control), Lys/Arg (250 mg Lys/250 mg Arg) and PAH (500 mg), respectively. The results are presented in Tables 1 to 3.

TABLE-US-00001 TABLE 1 Kidneys radioactivity [in % of injected radioactivity, decay corrected data] with co-infusion of 0.9% NaCl (control) Time (hour) rat04 rat05 rat06 average stdev 0.5 21.60% 4.80% 13.50% 13.30% 8.40% 1 19.70% 3.30% 13.70% 12.20% 8.30% 4 2.70% 2.70% 2.70% 2.70% 0.00% 8 2.70% 2.70% 2.70% 2.70% 0.00% 24 2.40% 2.30% 2.40% 2.40% 0.10%

TABLE-US-00002 TABLE 2 Kidneys radioactivity [in % of injected radioactivity, decay corrected data] with co-infusion of Lys/Arg (250 mg Lys/250 mg Arg) Time (hour) rat04 rat05 rat06 average stdev 0.5 13.30% 10.20% 12.50% 12.00% 1.60% 1 16.20% 10.50% 9.60% 12.10% 3.60% 4 2.60% 1.60% 2.10% 2.10% 0.50% 8 2.40% 1.60% 2.00% 2.00% 0.40% 24 2.30% 1.50% 1.80% 1.90% 0.40%

TABLE-US-00003 TABLE 3 Kidneys radioactivity [in % of injected radioactivity, decay corrected data] with co-infusion of PAH (500 mg) Time (hour) rat04 rat05 rat06 average stdev 0.5 6.10% 4.60% 9.10% 6.60% 2.30% 1 5.00% 5.00% 9.80% 6.60% 2.80% 4 1.30% 1.30% 1.60% 1.40% 0.20% 8 1.30% 1.20% 1.10% 1.20% 0.10% 24 1.10% 1.20% 1.10% 1.20% 0.00%

[0187] The values presented in Tables 1 to 3 are graphically illustrated in FIGS. 1 to 4.

[0188] As it is obvious from the presented results, co-infusion of Lys/Arg resulted in kidney uptake reduction of 21% and 26% after 8 h and 24 h, respectively, with a high variation between individuals (Table 2, FIGS. 1, 2 and 4). The outcome of amino acid infusion was similar to what is reported in the literature (33%+/−23%, Rolleman E J et al., supra). In contrast, co-infusion of PAH resulted in a reduction of 56% and 50% at the same time points with a low standard deviation (Table 3, FIGS. 1 and 2,). Infusions of PAH also result in lower kidney uptakes at early time points. At 0.5 h post injection the Lys/Arg mixture showed only minor reduction of 10% in contrast to PAH which showed a reduction of 50% (Tables 2 and 3, FIGS. 1-3).

Example 2: Ex Vivo Organ Uptake of [.SUP.177.Lu-DOTA.SUP.o.-Tyr3]-octreotide

[0189] Ex-vivo organ concentration of [.sup.177Lu-DOTA.sup.o-Tyr3]-octreotide was determined at an early time points of 5 min and 60 min p.i. according to the above protocol. The results are graphically illustrated in FIG. 5. Even at early time points, the uptake of [.sup.177Lu-DOTA.sup.o-Tyr3]-octreotide was significantly reduced (P 0.005) with respect to NaCl infusions when using PAH-infusions as a co-medication in comparison to Lys/Arg.

[0190] In summary, the above results demonstrate that sodium aminohippurate solutions have a significant higher effect in reducing renal retention and uptake of [.sup.177Lu-DOTA.sup.o-Tyr3]-octreotide than a combination of Lysine and Arginine known from the prior art.

Experimental Protocols (Examples 3-5)

[0191] The imaging study was designed to evaluate the effectiveness of PAH in reducing the renal uptake of peptides labeled with either .sup.177Lu or .sup.68Ga which were coordinated by chelators of distinct structures and binding scaffolds. The tracer distribution of the radiolabeled test compounds were performed in two distinct cohorts of healthy Wistar rats with focus on the kidney uptake/clearance and blood levels. One cohort was administered with the .sup.177Lu/.sup.68Ga-tracer in combination with saline for control (MBq/kg and mg/kg to be defined individually), while the other cohort first received an intraperitoneal injection of PAH (10 min prior to inj.) before administration of the .sup.177Lu/.sup.68Ga-peptide together with two intravenous injections of PAH solution. The kidney clearance and the overall pharmacokinetic of each .sup.177Lu/.sup.68Ga-peptide (administered with or without pre-dose of PAH) were assessed using PET or SPECT. Each cohort comprises at least 3 rats for statistic matters.

[0192] .sup.177Lu-peptides: .sup.177Lu labeled compounds provided by ITG were tested for radiochemical purity upon receipt using iTLC. Testing parameters were provided for each compound, RCP >95%. The nominal dose level, concentration and volume for each .sup.177Lu-peptide to be investigated are summarized in Table 4.

TABLE-US-00004 TABLE 4 .sup.177Lu-test Saline Group Ki group compound (0.9% NaCl) (200 mg/mL) No. animals 3 3 i.p. injection 2.0 mL 2.0 mL @ 0 min Bolus injection 0.5 mL + 0.5 mL + i.v. + .sup.177Lu- 50 MBq .sup.177Lu- 50 MBq .sup.177Lu- test compound compound compound @ 10 min (0.1-0.2 mL) (0.1-0.2 mL) Bolus injection 0.5 mL 0.5 mL i.v. @ 11 min SPECT/CT (ROI/VOI) Kidney + Kidney + Blood (Heart) Blood (Heart) Measurement 0.5 h, 1 h, 0.5 h, 1 h, time points 4 h, 24 h p.i. 4 h, 24 h p.i. .sup.68Ga-peptides: .sup.68Ga labeled compounds were prepared directly prior to application and were tested for radiochemical purity using iTLC. (Labeling and QC testing parameters were provided for each compound, RCP >95%). The nominal dose level, concentration and volume for each .sup.68Ga-peptide to be investigated are summarized in Table 5.

TABLE-US-00005 TABLE 5 .sup.68Ga-test Saline Group Ki group compound (0.9% NaCl) (200 mg/mL) No. animals 3 3 i.p. injection @ 0 min 2.0 mL 2.0 mL Bolus injection i.v. + 0.5 mL + 0.5 mL + .sup.68Ga-test 35 MBq .sup.68Ga- 35 MBq .sup.68Ga- compound @ 10 min compound compound (0.1-0.2 mL) (0.1-0.2 mL) Bolus injection 0.5 mL 0.5 mL i.v. @ 11 min PET/CT (ROI/VOI) Kidney + Kidney + Blood (Heart) Blood (Heart) Measurement scheme Dynamic Dynamic measurement from measurement from 0-60 min p.i. 0-60 min p.i. Static Static measurement at 2 h measurement at 2 h and 4 h p.i. and 4 h p.i.

Example 3: Reduction of Kidney Uptake of Various Radiolabeled Compounds by Concomitant Administration of PAH

[0193] Mice were injected with four different molecules conjugated with the cyclic chelator DOTA and radiolabeled with therapeutic radionuclide Lutetium-177: .sup.177Lu-DOTA-RGD, .sup.177Lu-DOTA-Affilin, .sup.177Lu-DOTA-Sargastrin, and .sup.177Lu-DOTA-JR11, respectively, and co-injected with PAH (200 mg/mL) or saline (0.9% NaCl) as a control. The percentage of injected radioactivity present in the kidneys over time was determined according to the above protocol. The results are graphically illustrated in FIG. 6.

[0194] According to FIG. 6, there is a significant effect in reduction of kidney uptake by concomitant administration of PAH with all compounds tested, in particular with small peptides, such as DOTA-RGD, DOTA-JR11 and DOTA-Sargastrin. It is also obvious from FIG. 6 that the effect of reduction of kidney uptake is already present at early time points of 0.5 to 1 h after administration.

[0195] Therefore, the above experimental results show that administration of PAH reduces kidney uptake of various kinds of radiolabeled compounds, i.e. DOTA-linked peptides, peptidomimetics etc., which are accumulated in kidney via different mechanisms.

Example 4: Influence of PAH on the Blood Activities of Different Radiolabels Compounds

[0196] Mice were injected with four different molecules conjugated with the cyclic chelator DOTA and radiolabeled with therapeutic radionuclide Lutetium-177: .sup.177Lu-DOTA-RGD, .sup.177Lu-DOTA-Affilin, .sup.177Lu-DOTA-Sargastrin, and .sup.177Lu-DOTA-JR11, respectively, and co-injected with PAH (200 mg/mL) or saline (0.9% NaCl) as a control. The percentage of injected radioactivity present in blood over time was determined according to the above protocol. The results are graphically illustrated in FIG. 7.

[0197] According to FIG. 7, there is a significant increase of blood activity by co-injected PAH for Affilin. Therefore, while kidney uptake of Affilin is less prominently reduced by PAH versus the other compounds tested (cf. FIG. 6), the data indicate that at the same time blood activities of Affilin are increased by co-injection of PAH resulting in an enhanced bioavailability of the radiopharmaceutical.

Example 5: Influence of PAH on the Kidney Uptake and Blood Activity of .SUP.68.Ga-Labeled PSMA-11

[0198] Mice were injected with diagnostic .sup.68Ga-labeled PSMA-11 conjugated with acyclic chelator HBED-CC, and co-injected with PAH (200 mg/mL) or saline (0.9% NaCl) as a control. The percentage of injected radioactivity present in kidney (upper lane) and blood (lower lane) over time was determined according to the above protocol. The results are graphically illustrated in FIG. 8.

[0199] As shown in FIG. 8, there is a significant reduction of kidney uptake of .sup.68Ga-labeled HBED-CC conjugated PSMA-11 by concomitant administration of PAH. It is also obvious from FIG. 8 that the effect of reduction of kidney uptake is already present at early time points of 0.1, 0.5 and 1 h after administration.

[0200] Therefore, the above experimental results of Examples 3-5 show that administration of PAH reduces kidney uptake of various kinds of radiolabeled compounds having different carrier molecules (peptide, peptidomimetics, recombinant proteins), different chelators (cyclic chelator, acyclic chelator), and different radionuclides (therapeutic radionuclide, diagnostic radionuclide), respectively, and can therefore suitably be used for the reduction of nephrotoxic side effects of a number of radiolabeled and non-radiolabeled diagnostic and therapeutic compounds.

Example 6: Comparative Biodistribution Analysis of .SUP.177.Lu-DOTATOC Given Intravenously to Mice after Intraperitoneal Injection of PAH or Physiological Saline Solution

[0201] Somatostatin receptor positive pancreatic tumor bearing CD1 nude mice (AR24J) received an i.p. injection of 50 μL NaCl 0.9% (group A) or 50 μL PAH 20% (group B) exactly 10 minutes before i.v. injection of .sup.177Lu-DOTATOC/NaCl (group A) or .sup.177Lu-DOTATOC/PAH (group B) via the retro-orbital venous sinus. The nominal dose level, concentration and volume are summarized in Table 6.

TABLE-US-00006 TABLE 6 Test item .sup.177Lu-DOTATOC/ .sup.177Lu-DOTATOC/ NaCl 0.9% PAH 20% Mice strain AR42J tumor AR42J tumor mouse model mouse model Pre-dosing 10 min before NaCl 0.9% PAH 20% .sup.177Lu-DOTATOC (50 μL) (50 μL) injection .sup.177Lu-DOTATOC 0.2 0.2 injection volume (mL)* Concentration (MBq/mL)** 7.4-5.4 7.4-5.4 Dose (MBq/mouse)** 1.5-1.1 1.5-1.1 Number of mice/termination 3 3 time point Number of termination time 4 4 points Number of mice 12 12 *Individual dose volume was calculated using individual body weight recorded on the day of treatment, and individual volumes and exact time of treatment were recorded and kept in study files **Range of concentration and dose taking into account the radioactive decay of .sup.177Lu over a period of 3 days from the day of delivery

[0202] Mice (3 animals per group) were sacrificed at 0.5 h, 1 h, 2 h, and 4 h, respectively. The organs were quickly rinsed in 0.9% NaCl and dried before being weighed and counted to eliminate possible contaminating blood. Following organs/tissues were sampled or taken, weighed and counted for .sup.177Lu: blood, tumor, kidneys, liver, bladder (empty), heart, spleen, lungs, brain, muscle, stomach (without contents), small intestine (without contents), colon (without contents) residual carcass. Data from organ/tissue counting are expressed as percentage of injected dose (% ID/g)). The organs/tissues distribution results for .sup.177Lu-DOTATOC in NaCl 0.9% (Group A), as well as the organs/tissues distribution results for .sup.177Lu-DOTATOC with PAH (Group B) are graphically presented in FIG. 9.

[0203] According to FIG. 9 there is a significant decrease of .sup.177Lu-DOTATOC uptake in kidneys in group B (lower panel) which received .sup.177Lu-DOTATOC with PAH compared to group A (upper panel) which received .sup.177Lu-DOTATOC in NaCl. The decrease in renal uptake of the radiolabeled compound is particularly evident at early stages (0.5 h, 1 h) after injection of .sup.177Lu-DOTATOC. At the same time, .sup.177Lu-DOTATOC level of group B in tumor and blood are significantly increased compared to group A. Without wishing to be bound by specific theory, it is hypothesized that blockage of elimination of .sup.177Lu-DOTATOC via the kidneys by PAH leads to a prolongation of blood circulation of .sup.177Lu-DOTATOC and thus to an increased accumulation of the radiolabeled compound also at the tumor site. In summary, the results presented show an enhanced bioavailability of .sup.177Lu-DOTATOC which received .sup.177Lu-DOTATOC with PAH compared to group A which received .sup.177Lu-DOTATOC in NaCl.

Example 7: Comparative Biodistribution Analysis of .SUP.99m.Tc-Etarfolatide Given in Combination with PAH or Physiological Saline Solution

7.1 Radiolabeling of Etarfolatide

[0204] .sup.99mTc-Etarfolatide has the following chemical structure:

##STR00009##

[0205] The radiolabelling was carried out by a method derived from the teaching of Kim et al. (Ann Nucl Med 2016; 30:369-379). The ligand exchange method was employed by using tartrate as a co-ligand. In an eppendorf, 100 μg of Etarfolatide, 50 μl of tartrate solution (20 mg/50 μl in millipore water), and 80 μl of SnCl.sub.2 dihydrate solution were added (1 mg/ml in 0.01 M HCl solution). In a lead shielded fume hood, about 750 MBq (20 mCi) of freshly eluted .sup.99mTc-pertechnetate was added, and the reaction vial was heated in a water bath for 30 min at 100° C. and cooled to room temperature.

[0206] Radiolabeling efficiency and stability was determined using: (i) Instant thin layer chromatography-silica gel (ITLC-SG) with water (Rf of .sup.99mTc-Etarfolatide and free pertechnetate=0.9-1.0; Rf of colloid=0.0-0.1) and acetone (Rf of free pertechnetate=0.9-1.0; Rf of colloid and .sup.99mTc-Etarfolatide=0.0-0.1) as the mobile phases and (ii) RP-HPLC: Solvent A: 0.1% TFA in H.sub.2O. Solvent B: 0.1% TFA in AcCN; Gradient Elution, flow rate 1 mL/min.

[0207] On each day of experimentation, a new radiolabeling procedure was performed with approximately the same .sup.99mTc activity. RP-HPLC showed RCP=˜100%, while TLC showed a maximum colloid formation of 5% or less. Stability of .sup.99mTc-Etarfolatide was assessed by HPLC at 24 h post-preparation, and showed no loss of radiolabel.

[0208] The volume of the radiolabeled folate was measured to be 1300 μL, while the activity was 734 MBq (Day of experimentation: March 4th). A sample corresponding to 300 MBq (i.e. 15 MBq×20 mice) was prepared. 531 μL were taken from the radiolabeled folate, which was diluted with either 1469 μL Saline or 1469 μL PAH (2000 μL 99mTc-etarfolatide, 100 μL/15 MBq per mouse). Before injection, the sample was filtered through a 0.22 M sterile filter. The injected 15 MBq/mouse corresponds to 2.04 μg Etarfolatide/mouse (injected quantity of Etarfolatide was kept stable throughout the experiment).

[0209] Samples of .sup.99mTc-Etarfolatide diluted with both Saline or PAH were assessed immediately after preparation, as well as 24 h post-dilution, and showed no signs of loss of radiolabel, when assessed by HPLC (100% RCP), however TLC assessment showed that .sup.99mTc-Etarfolatide/PAH was stable (100% RCP), while .sup.99mTc-Etarfolatide/saline showed 14% colloid formation.

7.2 Preparation of PAH Solution

[0210] Weigh 2 g PAH sodium salt in a Corning Tube; Addition of 4 mL H.sub.2O; Vortex—partial dissolution of PAH; Addition of 20 μL NaOH (provided by ITG), Vortex—partial dissolution of PAH; Addition of 20 μL NaOH, Vortex—complete dissolution of PAH; Addition of 2 mL H.sub.2O, pH 10; Addition of 80 μL HCL 37% (in 20 μL increments), pH ˜6. The final volume of the resulting solution was measured and found to be 7100 μL, to which we added 2900 μL (all this in another Corning Tube), for a final solution of 2 g PAH in 10 mL H.sub.2O, i.e. 200 mg PAH/mL. After filtration through a 0.22 μM filter, the Corning tube was covered with aluminum foil and cooled.

7.3 Biodistribution Analysis

[0211] 30 mice (male and female) were randomly assigned to two groups.

[0212] Group A: The mice were injected with .sup.99mTc Etarfolatide diluted in PAH (2.04 μg Etarfolatide/mouse) after having received an IP injection of PAH 10 min prior to radiotracer injection. Five time-points were assessed: 5 min, 30 min, 1 h, 2 h, 4 h (3 mice per time-point).

[0213] Injected Doses at each time-point:

TABLE-US-00007 Time Mouse Injection (μCi) Corrected  5 min 13:14 0  5 min_1 197 197 13:26 12  5 min_2 194 199 14:19 65  5 min_3 166 188 30 min 12:06 0  30 min_1 249 249 12:10 4  30 min_2 230 232 12:14 8  30 min_3 217 220 60 min 13:46 0  60 min_1 181 181 14:00 14  60 min_2 181 186 14:06 20  60 min_3 184 191 120 min  12:05 0 120 min_1 355 355 12:13 8 120 min_2 367 373 12:41 36 120 min_3 317 340 240 min  10:28 0 240 min_1 420 420 10:33 5 240 min_2 431 435 10:37 9 240 min_3 417 424

[0214] Group B: The mice were injected with .sup.99mTc Etarfolatide diluted in saline (2.04 μg Etarfolatide/mouse) after having received an IP injection of saline 10 min prior to radiotracer injection. Five time-points were assessed: 5 min, 30 min, 1 h, 2 h, 4 h (3 mice per time-point).

[0215] Injected Doses at each time-point:

TABLE-US-00008 Time Mouse Injection (μCi) Corrected  5 min 13:54 0  5 min_1 364 364 14:03 9  5 min_2 384 391 14:28 34  5 min_3 310 331 30 min 14:03 0  30 min_1 170 170 14:23 10  30 min_2 155 158 14:40 37  30 min_3 171 184 60 min 12:34 0  60 min_1 414 414 12:43 9  60 min_2 460 468 13:29 55  60 min_3 378 420 120 min  11:18 0 120 min_1 326 326 11:22 4 120 min_2 326 329 11:26 8 120 min_3 324 329 240 min  10:50 0 240 min_1 385 385 11:01 11 240 min_2 364 372 11:21 31 240 min_3 354 376

[0216] The results of the biodistribution analysis are shown in FIG. 10. After 30 min, the decreased renal uptake of .sup.99mTc-Etarfolatide by the protective effect of PAH becomes prominent. Thus, the effects observed for the .sup.177Lu-based conjugate molecule are confirmed for a .sup.99mTc chelating conjugate molecule with .sup.99mTc having another valence status than tri-valent .sup.177Lu.

Example 8: Biodistribution Analysis of .SUP.177.Lu-Labelled PSMA I&T

[0217] The chemical structure of “PSMA I&T” is the following

##STR00010##

Test Articles for the Imaging Experiments

[0218]

TABLE-US-00009 Storage of TA: Room Temperature upon arrival Quantity of TA: 5 mL in vial TA Code: .sup.177Lu-ITG-PSMA I&T Test Article 7 May and 14 May 2019: .sup.177Lu-ITG-PSMA I&T Details: Dissolved in Sponsor's property formulation 550 MBq/mL Radioactive Concentration both cases TA Dosing: 50 MBq of radioactivity intended TA Administration Intravenous (systemic) administration Route: Kidney Para-amino-hippuric acid solution - Protection 200 mg/mL in water, pH = 5 for Agents: injection ‘PAH’ (KP1) Probenecid suspension - 300 μL doses each vial, containing 50 mg Probenecid pH = 7-8 (KP2) Volume Extension (VE): NaCl 0.9% solution: reference - volume extending physiological saline (top load administration as for all agents) Administration All groups received an intravenous infusion of Kidney of 2 mL of KP1 or VE during 1 min., 1 h before Protection the application of the TA. One hour later this Agents: was followed by the intravenous injection of TA. At the end of this TA injection another 0.5 mL KP1 or VE was injected intravenously to each animal during a 1-minute period. In the case of KP2, the suspension in 0.4 mL volumes was orally gavaged to each rat 60 minutes before the aforementioned iv. TA injection. Imaging Time 30 min, 1 h, 2 h, 4 h hours post injection Points:

Measurement Systems and Parameter Settings for the Imaging Experiments

[0219]

TABLE-US-00010 SPECT Mediso NanoSPECT/CT Silver Upgrade imaging system, (Mediso Kft Budapest Hungary) instrument: Serial nr. NS004048-4RCT Mediso MultiCell compatible animal anaesthesia holder Calibration of 7 May 2019 SPECT: Calibration .sup.177Lu solution of known volume source: and radioactivity imaged with the same parameter settings as for the rat SPECT quantitative image acquisitions Calibration Nucline (Mediso) Quantitative Calibration Software: routine v 2.01 build 16 defining the calibration factor between reconstructed SPECT data and dose calibrator activities Radioactivity Dose MED 2010 (MED Nuklearmedizintechnik, Calibrator Type: Dresden, Germany) Serial nr. 92109 Dose Calibrator 17 Jun. 2017 in-factory calibration Calibration: performed and attested by the manufacturer ITLC Radioactivity miniGita Star (Raytest GmbH) Scan Detector Serial nr. 1501129 Type: HPLC System: Jasco LC-NET-II/ADC (Jasco Corp. Japan) Serial nr. B439161095

Execution of Protocol

[0220] The protocol was executed in a way to test the radioactivity concentration of the kidneys in groups of animals injected with one TA but three different KP agents in three separate groups. Thus, the following matrix of experimental groups was formed.

TABLE-US-00011 TA injection: .sup.177Lu-PSMA I&T KP or VE injected: NaCl PAH Probenecid Number of animals: 3 3 3 Resulting Subgroup Code: PSMA I&T - PSMA I&T - PSMA I&T - Saline PAH Probenecid

[0221] 1. Data of the PSMA I&T-Probenecid Imaging Experiment

TABLE-US-00012 1.1. Rat 1 Species, strain: Laboratory Rat (Rattus norwegicus), Lewis Number at start: N/A Included number: N/A Internal animal Rat 49: 278 g Group Code for Imaging: code weight and sex: 233 PSMA I&T-Probenecid KP procedure: Probenecid administration KP agent quantity: 0.4 mL KP agent injection times: Per os administered TA volume of tail 0.11 vein administration (mL): TA solution injection 9:42 start time: Measured activity 50.4  at administration (MBq): Imaging time: 0.5 h, 1 h, 2 h, 4 h Hours and dates of 0.5 h 1 h 2 h 4 h SPECT imaging start

TABLE-US-00013 1.2. Rat 2 Species, strain: Laboratory Rat (Rattus norwegicus), Lewis Number at start: N/A Included number: N/A Internal animal Rat 50: 290 g Group Code for Imaging: code weight and sex: 234 PSMA I&T-Probenecid KP procedure: Probenecid administration KP agent quantity: 0.4 mL KP agent injection times: Per os administered TA volume of tail 0.11 vein administration (mL): TA solution injection 12:12 start time: Measured activity 50.7  at administration Imaging time: 0.5 h, 1 h, 2 h, 4 h Hours and dates of 0.5 h 1 h 2 h 4 h SPECT imaging start

TABLE-US-00014 1.3.Rat 3 Species, strain: Laboratory Rat (Rattus norwegicus), Lewis Number at start: N/A Included number: N/A Internal animal Rat 51: 278 g Group Code for Imaging: code weight and sex: 235 PSMA I&T-Probenecid KP procedure: Probenecid administration KP agent quantity: 0.4 mL KP agent injection times: Per os administered TA volume of tail 0.115 vein administration (mL): TA solution injection 11:24 start time: Measured activity 52.1   at administration Imaging time: 0.5 h, 1 h, 2 h, 4 h Hours and dates of 0.5 h 1 h 2 h 4 h SPECT imaging start

[0222] 2. Data of the PSMA I&T-PAH Imaging Experiment

TABLE-US-00015 2.1 Rat 4 Species, strain: Laboratory Rat (Rattus norwegicus), Lewis Number at start: N/A Included number: N/A Internal animal Rat 52: 291 g Group Code for Imaging: code weight and sex: 236 PSMA I&T-PAH KP procedure: PAH injection KP agent quantity: 2 mL + 0.5 mL + 0.5 mL KP agent injection times: Intraperitoneally & Intravenously administered TA volume of tail 0.12 vein administration (mL): TA solution injection 6:31 start time: Measured activity 52.9  at administration Imaging time: 0.5 h, 1 h, 2 h, 4 h Hours and dates of 0.5 h 1 h 2 h 4 h SPECT imaging start

TABLE-US-00016 2.2 Rat 5 Species, strain: Laboratory Rat (Rattus norwegicus), Lewis Number at start: N/A Included number: N/A Internal animal Rat 53: 294 g Group Code for Imaging: code weight and sex: 237 PSMA I&T-PAH KP procedure: PAH injection KP agent quantity: 2 mL + 0.5 mL + 0.5 mL KP agent injection times: Intraperitoneally & Intravenously administered TA volume of tail 0.12 vein administration (mL): TA solution injection 9:01 start time: Measured activity 52.1  at administration Imaging time: 0.5 h, 1 h, 2 h, 4 h Hours and dates of 0.5 h 1 h 2 h 4 h SPECT imaging start

TABLE-US-00017 2.3 Rat 6 Species, stain: Laboratory Rat (Rattus norwegicus), Lewis Number at start: N/A Included number: N/A Internal animal Rat 59: 314 g Group Code for Imaging: code weight and sex: 242 PSMA I&T-PAH KP procedure: PAH injection KP agent quantity: 2 mL + 0.5 mL + 0.5 mL KP agent injection times: Intraperitoneally & Intravenously administered TA volume of tail 0.11 vein administration (mL): TA solution injection 12:46 start time: Measured activity at 53.1  administration Imaging time: 0.5 h, 1 h, 2 h, 4 h Hours and dates of 0.5 h 1 h 2 h 4 h SPECT imaging start

[0223] 3. Data of the PSMA I&T-Saline Imaging Experiment

TABLE-US-00018 3.1 Rat 7 Species, strain: Laboratory Rat (Rattus norwegicus), Lewis Number at start: N/A Included number: N/A Internal animal Rat 55: 324 g Group Code for Imaging: code weight and sex: 239 PSMA I&T-Saline KP procedure: Saline injection KP agent quantity: 2 mL + 0.5 mL + 0.5 mL KP agent injection times: Intraperitoneally & Intravenously administered TA volume of tail vein 0.1 administration (mL): TA solution injection 11:52 start time: Measured activity at 52.8  administration Imaging time: 0.5 h, 1 h, 2 h, 4 h Hours and dates of 0.5 h 1 h 2 h 4 h SPECT imaging start

TABLE-US-00019 3.2 Rat 8 Species, stain: Laboratory Rat (Rattus norwegicus), Lewis Number at start: N/A Included number: N/A Internal animal Rat 56: 299 g Group Code for Imaging: code weight and sex: 240 PSMA I&T-Saline KP procedure: Saline injection KP agent quantity: 2 mL + 0.5 mL + 0.5 mL KP agent injection times: Intraperitoneally & Intravenously administered TA volume of tail vein 0.1 administration (mL): TA solution injection 10:11 start time: Measured activity at 51.5  administration Imaging time: 0.5 h, 1 h, 2 h, 4 h Hours and dates of 0.5 h 1 h 2 h 4 h SPECT imaging start

TABLE-US-00020 3.3 Rat 9 Species, strain: Laboratory Rat (Rattus norwegicus), Lewis Number at start: N/A Included number: N/A Internal animal code Rat 58: 322 g Group Code for Imaging: weight and sex: 241 PSMA I&T-Saline KP procedure: Saline injection KP agent quantity: 2 mL + 0.5 mL + 0.5 mL KP agent injection Intraperitoneally & times: Intravenously administered TA volume of tail 0.11 vein administration (mL): TA solution injection 10:16 start time: Measured activity 51.5  at administration Imaging time: 0.5 h, 1 h, 2 h, 4 h Hours and dates of 0.5 h 1 h 2 h 4 h SPECT imaging start

Results

PE1: Toxicity Observations

[0224] Result: No sign of acute immediate and delayed acute toxicity was observed.

PE2: Radioactivity Accumulation Over Time in the Organs

[0225]

TABLE-US-00021 No. Primary Endpoint Data Type Data Units Data Measurement Method PE2 Decay corrected radioactivity concentration MBq: SPECT image analysis by means of and proportion of the organ radioactivity MBq/cm.sup.3; calibrated SPECT system, MRI concentration to the administered % organ images as templates for radioactivity concentration in %, in the Volumes of Interest and the following organs: VivoQuant v. 1.22 software Kidneys (whole), renal medullae, renal cortices, heart left ventricle for blood [0226] Result: the following, tables per time point contain the decay corrected radioactivity concentration ratio in the sum of both kidneys in % of the injected whole body radioactivity concentration.

TABLE-US-00022 TABLE I Results-Kidney radioactivity in percentage of injected radioactivity in the group injected with .sup.177Lu.sup.—PSMA I&T and receiving the Probenecid suspension po. Probenecid kidney radioactivity [in % of injected radioactivity, decay corrected data] Rat49 Rat50 Rat51 time left right left right left right average stdev 0.5 h   20.0% 20.0% 18.1% 19.7% 18.8% 20.1% 19.4% 0.8% 1 h 20.3% 20.8% 19.4% 19.9% 16.8% 17.8% 19.2% 1.5% 2 h 15.0% 15.3% 14.5% 14.7% 13.5% 14.0% 14.5% 0.7% 4 h 9.2% 9.4% 9.1% 9.5% 10.6% 10.2% 9.7% 0.6%

TABLE-US-00023 TABLE II Results-Kidney radioactivity in percentage of injected radioactivity in the group injected with .sup.177Lu.sup.—PSMA I&T and receiving PAH solution ip. and iv. PAH kidney radioactivity [in % of injected radioactivity, decay corrected data] Rat52 Rat53 Rat59 time left right left right left right average stdev 0.5 h   14.4% 16.0% 15.5% 15.3% 14.0% 13.6% 14.8% 0.9% 1 h 12.6% 13.8% 14.5% 14.7% 12.9% 12.6% 13.5% 1.0% 2 h 9.0% 9.7% 9.2% 9.1% 9.8% 9.4% 9.4% 0.3% 4 h 5.2% 5.7% 5.7% 6.2% 6.4% 6.3% 5.9% 0.5%

TABLE-US-00024 TABLE III Results-Kidney radioactivity in percentage of injected radioactivity in the group injected with .sup.177Lu.sup.—PSMA I&T and receiving the Saline ip. and iv. Saline kidney radioactivity [in % of injected radioactivity, decay corrected data] Rat55 Rat56 Rat58 time left right left right left right average stdev 0.5 h   19.5% 18.5% 15.1% 17.3% 19.5% 18.7% 18.1% 1.7% 1 h 17.9% 17.5% 17.6% 18.9% 16.7% 15.9% 17.4% 1.0% 2 h 14.0% 13.7% 15.2% 16.0% 12.3% 11.5% 13.8% 1.7% 4 h 8.7% 8.5% 9.5% 9.8% 7.5% 7.4% 8.6% 1.0%

TABLE-US-00025 TABLE IV Results-Blood (left ventricle) radioactivity in percentage of injected radioactivity in the group injected with .sup.177Lu-PSMA I&T and receiving the Probenecid suspension po. Probenecid blood radioactivity [in % of injected radioactivity decay corrected data] time Rat49 Rat50 Rat51 average stdev 0.5 h   3.3% 2.7% 2.9% 3.0% 0.3% 1 h 1.8% 1.7% 2.2% 1.9% 0.3% 2 h 1.0% 1.1% 1.3% 1.1% 0.2% 4 h 0.4% 0.4% 0.6% 0.5% 0.2%

TABLE-US-00026 TABLE V Results-Blood (left ventricle) radioactivity in percentage of injected radioactivity in the group injected with .sup.177Lu-PSMA I&T and receiving PAH solution ip. and iv. PAH blood radioactivity [in % of injected radioactivity, decay corrected data] time Rat52 Rat53 Rat59 average stdev 0.5 h   2.1% 3.2% 2.4% 2.5% 0.6% 1 h 1.4% 1.7% 1.9% 1.6% 0.3% 2 h 0.6% 0.8% 1.1% 0.8% 0.2% 4 h 0.3% 0.4% 0.6% 0.4% 0.2%

TABLE-US-00027 TABLE VI Results-Blood (left ventricle) radioactivity in percentage of injected radioactivity in the group injected with .sup.177Lu-PSMA I&T and receiving Saline ip. and iv. Saline blood radioactivity [in % of injected radioactivity, decay corrected data] time Rat55 Rat56 Rat58 average stdev 0.5 h   2.7% 3.8% 2.6% 3.0% 0.7% 1 h 1.7% 2.5% 1.7% 2.0% 0.5% 2 h 1.1% 1.3% 1.0% 1.1% 0.1% 4 h 0.5% 0.5% 0.4% 0.5% 0.1%

TABLE-US-00028 TABLE VII Results-Renal medulla radioactivity in percentage of injected radioactivity in the group injected with .sup.177Lu.sup.—PSMA I&T and receiving the Probenecid suspension po. Probenecid kidney radioactivity [in % of injected radioactivity, decay corrected data] Rat49 Rat50 Rat51 time left right left right left right average stdev 0.5 h   2.6% 2.7% 2.4% 2.5% 2.4% 2.7% 2.6% 0.1% 1 h 2.6% 2.8% 2.8% 2.7% 2.2% 2.3% 2.6% 0.3% 2 h 2.0% 2.0% 1.9% 1.9% 1.8% 1.9% 1.9% 0.1% 4 h 1.2% 1.2% 1.2% 1.2% 1.4% 1.3% 1.2% 0.1%

TABLE-US-00029 TABLE VIII Results-Renal medulla radioactivity in percentage of injected radioactivity in the group injected with .sup.177Lu.sup.—PSMA I&T and receiving PAH solution ip. and iv. PAH kidney radioactivity [in % of injected radioactivity, decay corrected data] Rat52 Rat53 Rat59 time left right left right left right average stdev 0.5 h   2.0% 2.2% 2.1% 2.2% 1.9% 2.0% 2.0% 0.1% 1 h 1.6% 1.8% 1.9% 1.8% 2.0% 2.6% 2.0% 0.4% 2 h 1.1% 1.1% 1.2% 1.2% 1.4% 1.3% 1.2% 0.1% 4 h 0.7% 0.8% 0.7% 0.8% 0.9% 0.8% 0.8% 0.1%

TABLE-US-00030 TABLE IX Results-Renal medulla, radioactivity in percentage of injected radioactivity in the group injected with .sup.177Lu.sup.—PSMA I&T and receiving the Saline ip. and iv. Saline kidney radioactivity [in % of injected radioactivity, decay corrected data] Rat55 Rat56 Rat58 time left right left right left right average stdev 0.5 h   2.6% 2.5% 2.1% 2.3% 2.6% 2.5% 2.4% 0.2% 1 h 2.3% 2.4% 2.3% 2.5% 2.1% 2.4% 2.3% 0.1% 2 h 1.8% 1.8% 2.2% 2.5% 1.6% 1.6% 1.9% 0.4% 4 h 1.2% 1.1% 1.2% 1.3% 1.0% 1.0% 1.1% 0.1%

TABLE-US-00031 TABLE X Results-Renal cortex radioactivity in percentage of injected radioactivity in the group injected with .sup.177Lu.sup.—PSMA I&T and receiving the Probenecid suspension po. Probenecid kidney radioactivity [in % of injected radioactivity, decay corrected data] Rat49 Rat50 Rat51 time left right left right left right average stdev 0.5 h   17.4% 17.3% 15.7% 17.2% 16.3% 17.3% 16.9% 0.7% 1 h 17.7% 18.0% 16.6% 17.2% 14.6% 15.5% 16.6% 1.3% 2 h 13.0% 13.2% 12.7% 12.7% 11.7% 12.1% 12.6% 0.6% 4 h 8.0% 8.2% 7.9% 8.3% 9.2% 8.9% 8.4% 0.5%

TABLE-US-00032 TABLE XI Results-Renal cortex radioactivity in percentage of injected radioactivity in the group injected with .sup.177Lu.sup.—PSMA I&T and receiving PAH solution ip. and iv. PAH kidney radioactivity [in % of injected radioactivity, decay corrected data] Rat52 Rat53 Rat59 time left right left right left right average stdev 0.5 h   12.5% 13.8% 13.4% 13.1% 12.1% 11.7% 12.8% 0.8% 1 h 11.0% 12.0% 12.6% 12.8% 10.8% 9.9% 11.5% 1.1% 2 h 7.9% 8.5% 8.0% 7.9% 8.5% 8.1% 8.1% 0.3% 4 h 4.5% 5.0% 4.9% 5.4% 5.5% 5.5% 5.1% 0.4%

TABLE-US-00033 TABLE XII Results-Renal cortex radioactivity in percentage of injected radioactivity in the group injected with .sup.177Lu.sup.—PSMA I&T and receiving the Saline ip. and iv. Saline kidney radioactivity [in % of injected radioactivity, decay corrected data] Rat55 Rat56 Rat58 time left right left right left right average stdev 0.5 h   16.9% 16.0% 13.0% 14.9% 16.9% 16.2% 15.7% 1.5% 1 h 15.6% 15.1% 15.3% 16.4% 14.5% 13.5% 15.1% 1.0% 2 h 12.2% 11.9% 13.0% 13.5% 10.7% 9.9% 11.9% 1.4% 4 h 7.5% 7.4% 8.3% 8.5% 6.5% 6.5% 7.4% 0.8%

[0227] The results are depicted by FIGS. 11 to 14. All experiments show a marked reduction of radioactivity in kidney cells upon administration of PAH as compared to the saline control and also compared to the probenecid control experiment (FIG. 11). Both the renal cortex (FIG. 13) and the renal medulla (FIG. 14) show a reduced radioactivity at all time points in the course of the experiment upon administration of PAH.

[0228] Probenecid was tested as a further control. Probenecid was known as a strong inhibitor of OA.sup.− (organic anions) secretion of the proximal tubular cells of the kidney. It inhibits the organic anion transporter Type 1 (OAT1) at the basolateral side of the cell. OAT1 is known for its uptake of organic anions from the blood into the kidney tubular cells in exchange with dicarboxylates, e.g. succinate or 2-oxoglutarate. The experiments according to Example 8 (see FIGS. 11 to 14) all shows no effect of the probenecid-based inhibitory mechanism on OAT1. Thus, it is to be concluded that the PAH-based effects on decreasing radioactivity in kidney cells are based on another mechanism than known for probenecid.