CZ382399A3 - Stents, radioactive coated on surface, process of their preparation and their use in prophylaxis of restenosis - Google Patents

Abstract

Radioactive stents are coated on the surface radioactive isotopes, fixed by a substance, mediating adherence. The ways of their production lie immersing in a solution containing the radioactive isotope and its chemical exclusion. These stents are used for making implants for restenosis prophylaxis.

Description

Stents, coated on the surface, method of their production and their use in the prophylaxis of restenosis

Technical field

The invention relates to stent-coated stents, to a process for their manufacture and to their use for the prophylaxis of restenosis.

BACKGROUND OF THE INVENTION

Radioactive stents correspond to the state of the art (EP 0433011, WO 94/26205, US 5176617). Stents are endoprostheses that allow the opening of venous structures in human or animal bodies (for example, stents for blood vessels, osophages, trachea and bile ducts). They are used as palliative measures in constriction by occlusion (eg by atherosclerosis) or by external pressure (eg by tumors). Radioactive stents are used, for example, after vascular surgical interventions or after interventional radiological interventions (e.g. balloon angioplasty) for the prophylaxis of restenosis. Such radioactive stents can be produced, for example, by activation of a non-radioactive stent by irradiation with protons, or deuterons, from cyclotron (WO 94/26205). This method of manufacture is referred to as ion implantation.

The problem is that, on the one hand, the cyclotron is not usually available at the stent site to activate the stent and, on the other hand, the activated stent is not due to the partially short half-life of activated isotopes and because of radiation protection freely storable and transportable.

It is therefore an object of the present invention to provide stents and a novel process for their preparation which can be activated independently of the cyclotron. In particular, it is an object of the invention to provide stents which, independently of cyclotron, can be coated with a preselected radioactive isotope.

This task was solved by the stents described below and the method of their manufacture.

SUMMARY OF THE INVENTION

The above task was solved by the method of manufacturing radioactive stents described below. In contrast to ion implantation, the methods of manufacturing radioactive stents according to the invention are based on chemical or electrochemical methods.

Within the scope of the present invention, the radioactive isotopes of ⁿⁿ X and X-nn (X is the element mark and nn is the atomic number) (for example, corresponds to Ag-110) as synonyms will apply.

In the first variant, the above-described task has been solved by a method for producing radioactive stents in which the radioactive isotope on the stent is chemically excluded.

For this, the selected stent is immersed in a solution containing a radioactive isotope. The radioactive isotope is then chemically excreted on the stent. Depending on the selected stent material on the one hand and the secreted radioactive isotope on the other hand, two excretion options are possible.

0 • 0 »0> 0 • 00

1) Chemical reduction

For chemical reduction, a reducing agent (e.g., SnCl ₂ , KBH ₄ , dimethylborane, formaldehyde, sodium hypophosphite) is added to the solution containing the radioactive isotope in dissolved form as well as the stent.

Overview:

M ²⁺ + 2 e ~ (from reducing agent) -> catalytic surface -> Μθ

Reducing agent hypophosphite (for Ni) ^ 2 ^ θ2 ^{_ +} ^ 2θ - ^> catalytic surface -> HPO ₃ ² ~ + 2H ⁺ + H ^_

H '+ Ni ²⁺ -> NiH ₂

Addition of citrate, acetate, fluoride, succinate, lactate, propionate, pH = 4-11

Reducing agent NaBH ^ (for Au, Ni) bh ₄ ~ + h ₂ o -> bh ₃ oh ^_ + h ₂

BH-jOH '+ 3 Au (CN) ₂ + 3 OH'-> catalytic. surface ->

B0 ₂ ^_ +1.5 H ₂ 0 + 3 Au ° + 6 CN + 2 H ₂ 0

Ni ²⁺ + NaBH4 + 2 H20 -> Art. surface -> 2 Νίθ + 2 H2 + 4 H ⁺ + NaBO2

Addition of dimethylammonium borate, boric acid, citric acid, malonic acid, glycine, pyrophosphate, malic acid, pH = 4-10

Formaldehyde reducing agent: (for Cu)

Cu ²⁺ + 2 HCOH + 4 OH ^- -> catalytic. surface -> Cu ° + H ₂ > · + 2 H ₂ 0 + 2 HCOO "with added tartrate NaK, NaOH

Hydrazine reducing agent: (for Pd, Pt)

Pd, Pt with addition of NH 4 OH, EDTA

Dimethylborane (CH ₃ ) ₂ NH.BH ₃ reducing agent: (for Au, Ag) (CH ₃ ) ₂ NH.BH ₃ + OH "-> catalytic. surface -> BH ₃ OH '+ (ch ₃ ) ₂ nh

Au and Ag from cyanide baths

After one minute to ten hours, the stent is removed from the solution and washed. The stent is coated on the surface with a radioactive isotope.

For example, radioisotopes of the elements Ag, Au, Bi, Co, Cr, Cu, Fe, Gd, Hg, Ho,

In, Ir, Lu, Mn, Ni, P, Pb, Pd, Pm, Pt, Re, Rh, Ru, Se, Sm,

Tb, Tc or Y on metal stents (eg steel, Nitinol).

2) Chemical precipitation

In chemical precipitation, a precipitant (for example, oxalic acid, phosphoric acid, or salts thereof, or Na ₂ CO ₃ ) is added to the solution containing the radioactive isotope in dissolved form as well as the stent.

For example, radioisotopes of the elements Ag, Au, Bi, Co, Cr, Cu, Fe, Gd, Hg, Ho,

In, Ir, Lu, Mn, Ni, Pb, Pd, Pm, Pt, Re, R, R, Ru, Sc, Sm, Tb,

Tc or Y on metal stents (eg steel, Nitinol).

• 4,444

4 44 * 4 4 · 4 4 _t 9 9 4 · 4 4 4 · t? 4 4 4 4 4 4

J 44444

4444 44 444 «44 ·· 44

In the second variant, the above-described object has been achieved by fixing the radioactive isotope to the stent surface by means of an adhesion promoter.

Thus, the arrangement according to the invention consists of a metal stent body, an agent mediating adhesion to the stent surface and a radioactive isotope adhered thereto.

Commercial vascular implants such as Viktor stent, Strecker stent, or Palmaz-Schatz stent may be used as the base.

As adhesion promoters, peptides, fats, or gold may be used in combination with a thiol-group-containing complexing agent.

For example, it is possible to use modified polyurethanes which themselves contain complexing agents.

However, peptides which both carry a complexing agent and specifically bind to the stent metal can also be used as a tackifier. By way of example, these compounds are labeled endothelin derivatives as described, for example, in EP 606683, DE 4425778, DE 43 37 600, DE 43 37 599, and DE 19652374 (e.g. Tc-99m-Asp-Gly-Gly-Cys-Gly-Cys-Phe- (Dr-Trp) -Leu-Asp-Ile-Ile-Trp).

Fats which carry a mono-complexing agent can also be used as a tackifier. Examples of these are complexing agents carrying lipophilic residues, which are disclosed in DE 43 40 809, EP 450742,

EP 438206, EP 413405 or WO 96/26182.

999 999 9

9 9 9 9 9 9 4 · 44

4 9 4 9 4 9 4 f, 4 ’9 4 9 4 9 994 944 ···· 44 999 499 49 99

In addition, gold in combination with a thiol-containing complexing agent can also be used as a sticking agent. Compounds with a thiol group are known to exhibit increased affinity for gold-coated surfaces (H. Schonherr et al. J. Am. Chem. Soc. 118, (1996) 13051-13057). Surprisingly, the elemental gold present on the surface of the stent is also capable of fixing specific complexing agents if they contain thiol groups. Complexing agents then fix the radioactive isotopes themselves.

Complexing agents within the meaning of this specification, include DTPA, DOTA, D03A, EDTA, TTHA, amides MAG _2> MAG3 amides and their derivatives.

As radioactive isotopes, the radioactive isotopes of the elements Ag, Au, Ba, Bi, C, Co, Cr, Cu, Fe, Gd, Hg, Ho, In, Ir, Lu, Mn, Ni, Pb, Pd, Pm , Pt, Re, Rh, Ru, S, Sb, Sc, Sm, Tb, Tc or Y.

The invention thus relates to radioactive stents and is characterized in that the radioactive isotope is fixed on the surface of the stent by means of an adhesion promoter.

For example, the stents of the invention may be prepared as follows:

A. Peptide as an adhesion promoter

First, a peptide is selected which is itself capable of complexing heavy metal ions. This is activated by a β A reaction with a radioactive isotope (for example Re or 1888 ° Re), optionally together with a reducing agent.

• · φφφφ φφφ φφ

The radiolabeled peptide is dissolved in a solvent (e.g., water or phosphate buffer) and the stent is immersed in its solution. After removal from the peptide solution, the stent is dried in an oven at room temperature. After washing, the stent is ready for use.

A.2 In a process variant, the uncoated stent is first coated with an unactivated peptide. The coated stent is then immersed in a solution containing a radioactive metal (for example, 1 R or R 2, optionally together with a reducing agent (for example SnCl 3)) and so saturated with the isotope.

B. Fat as an adhesion promoter

The uncoated stent is first coated with a lipophilic compound (e.g., 3,9-bis (carboxymethyl) -6-bis- (octadecyl) aminocarbonylmethyl-3,6,9-triazaundecanoic acid, WO 96/26182) as an adhesion promoter. This lipophilic compound carries the remainder of DTPA as a complexing agent. The stent may be dipped directly into this compound or into a solution thereof. The compound-coated stent is then reacted with a radioactive metal solution (e.g., θ). After washing, the stent is ready for use.

B.2 In one variation of this procedure, the stent is coated in two stages. To do this, the stent is first treated with a lipophilic compound having amino groups. Then, the amino groups are reacted with DTPA monoanhydride as described in the literature. The stent is now coated with a complexing agent (here DTPA). This coated stent

444444 4 · ·· ··· 4 4 44 ·· ····

4 4444

44 4 4 444444

4 4 4 4 4 5

The 4444 44 4 · 4444 44 44 is then reacted with a solution of radioactive metal (for example ®YCl 3). After washing, the stent is ready for use. of

UZltl.

C. Gold / complexing agent containing thiol groups as a adhesion promoter

C.l Uncoated stent is first coated with electrochemically elemental gold (internal electrolysis, cementation). The gold-coated stent is then immersed in an aqueous solution of a thiol-group-containing complexing agent (e.g., N, N-dimethyl-2- (3,3,5,11,13,13-hexamethyl-1,2-dithia-5,8,11- triazacyclotridecan-8-yl) -ethylamine, or the product of the coupling of 11-amino-undecyl-1-thiol with bis-anhydride (DTPA). The thiol-group-containing complexing agent adheres to the gold-coated stent. The stent thus prepared is now reacted with a solution of radioactive metal (e.g., Cu2SO4). After washing, the stent is ready for use.

The complexing agent can be synthesized on the stent surface. It is possible to first apply only one part of the complexing agent to the gold coated stent and then bind this part with other sub-parts. This method is described in detail in the examples.

C.2 In one variation of this process, the gold-coated stent is reacted with a solution of a thiol-group-containing complexing agent that already contains a complex with a radioactive isotope. After washing, the stent is ready for use.

C.3 In one variation of this procedure, the gold-coated stent is treated with a solution of a compound containing a thiol α r group which contains ^J S. After washing, the stent is ready for use.

C.4 In another variation of this process, the gold-coated stent is reacted with a solution of a complexing agent containing thiol groups, wherein the thiol group is labeled with the complexing agent already containing a radioactive isotope complex (e.g. ^{D /} Cu). After washing, the stent is ready for use.

The methods described above are generally carried out at temperatures of from 0-100 ° C. Solvents may be used to coat the stent with a tackifier, depending on the tackifier. If a non-aqueous solvent is used, this must be removed before implantation.

Stents may also be coated with two or more different isotopes. In particular, it is possible to apply isotopes of short and long lifetime together on one stent (e.g. 5 ^ Co with 55ρ _{ε> s} 68 £ _u , or 99jj _axis 57 (- < _ο )

The operations required to carry out the above-described methods are known to those skilled in the art. Special embodiments are described in detail in the examples.

The invention further relates to a third variant of a process for the production of radioactive stents, characterized in that the non-radioactive stent is immersed in a solution containing at least one radioactive isotope in ionic form and the isotope is then chemically deposited on the stent.

According to the invention, the above-described object is solved according to the invention

999 999

9

Electrochemical deposition of the radioactive metal isotope on the stent.

For this purpose, the selected stent is immersed in a solution containing a radioactive metal isotope. The radioactive isotope is then electrochemically eliminated. Depending on both the stent material and the radioactive isotope secreted, two excretion options are also contemplated.

I) Galvanization (external electrolysis)

During galvanization, the dissolved radioactive isotope is eliminated by reduction by applying direct current to a stent connected as a cathode.

For example, copper, technetium, rhenium can be deposited. silver or indium on electrically conductive stents (steel, nitinol).

II) Cementation (internal electrolysis)

During cementation, the dissolved noble isotope is deposited on the non-noble stent material without the introduction of electrical current due to the position of the materials in a number of standard metal potentials. Thus, for example, gold, silver or copper can be deposited on metal stents (e.g. steel, nitinol).

Two electrochemical processes have proven to be particularly suitable for coating metal stents: electroplating (electrolytic coating) and cementing (internal electrolysis). The most widely used method is galvanization, since it also allows the coating to be electrochemically negative

4444

44 • · · tt 4 4 4 · 4 · 4 4 4 4 · 44444444 · 4 4 4 4

4444 44 444 444 44 44 materials other than stent. The coating also allows chemical processes - for example, reduction processes.

In terms of user acceptability, cementation is a better procedure: the stent is embedded in a solution of an electrochemically more positive element and is coated without external current.

By suitably arranging the cells, the excess coating material can be kept small. The necessary stirring can be induced by a magnetic stirrer or by manual stenting. Since only small amounts of material are applied in this process, manual mixing is possible. The same applies to reactions at elevated temperature: in a short time, thermostatization is not necessary, but preheating is sufficient.

The filling of the cuvettes (Fig. 1, 2) can be carried out by means of syringes or, for larger stents, by means of metering pumps. In these larger cells, it is expedient to separate the used electrolyte solution (active) and the wash liquid (inactive) to maintain a small volume of the active liquid.

In the cuvettes arranged in Figures 1, 2, the stent and its carrier are placed in a receptacle, maintaining the elevated position with the groove. This groove comprises, in the case of a galvanizing cell, a platinum sheet, as a contact for a stent, connected as a cathode. There is a platinum width on the cell wall as an anode. By using a metal ring of another metal which is conductively connected to the anode, a tin, zinc or copper anode can be used.

The use of stents with its carrier has the advantage that the inner side of the stents is shielded and so that there is no coating. The bedding will only occur at the points that are facing.

• To the container. Since restenosis is suppressed by the coating, the electrolytic polishing of the raw stent can be eliminated, especially in the case of stainless steel.

Possibilities of electrochemical marking of stents

Galvanostatic excretion

For this purpose, a battery (1.5-12 V), which is connected to a variable resistor and 2 electrode terminals, is sufficient. The coated metal is connected as a cathode. A noble metal, preferably platinum, should be used as the anode. The electrolysis time is 20 seconds to 30 minutes. The reaction is carried out at temperatures of from 0 to 80 ° C, preferably at room temperature.

Cu: (for example Cu-67, β and gamma, tg / g ⁼ 61.9 h) from pyrophosphate baths of this composition

Cu ²⁺ (P ₂ O ₇ ) ⁴ no ₃ nh ₃ (hpo ₄ ) ² pH

20-40 g 15-250 g 5-10 g 1-3 g <110 g 8-9

1-8 A / dm ² from CuCN alkaline baths at pH 12,2-12,8 from acid baths

- sulphate-oxalate-boric acid

- CuCl / sodium thiosulfate frfrfr frfr fr frfrfr frfrfr frfrfr frfrfr frfrfr frfrfr frfrfr frfrfr frfrfr frfrfr

I · fr · ·

- fluoroborate, fluorosilicate, formate

- copper gluconate, lactate, maleate, tartrate I = 1-2,5 A / dm ²

U = 0.2-6 In pH = 1.2

Au: (Au-199, t - ^ / ₂ = ² 'beta and gamma) from cyanide bath with phosphate and citrate addition at pH 5-12 from NH ₄ C1KAuCN ₂ bath with thiourea addition at pH

6,5-7,

I = 0.1-0.6 A / dm ²

In: from cyanide bath at pH = 0-1 from fluoroborate bath with tartaric acid addition at pH = 1

The pH is 2-3 or sulfamate and tartrate

Re: from perrhenate Re-186 citrate + H2SO4, pH 1-5 I = 1-15 A / dm ²

Ni: from NiSO4 / boric acid or from baths of acetate, fluoroborate or sulfamate pH = 1-5

I = 2-30 A / dm ²

Pt, Rh, Pd, Ru

(Pt-197, t _1/2 = β)

I = 1-4 A / dm ²

Ru from (NH ₂ ) 4 (Ru ₂ NCyg (H ₂ 0) ₂ ) or from sulfamate Rh from sulfate or phosphate with H ₂ SO 4

9,999 • 9 9 9

9 9 9 •

• ·

PH: 1-2

Pd from Pd (NH ₃ ) ₄ Br ₂ , EDTA

Pt from H ₂ Pt (NO ₂ ) 2§θ4 ^{with the} addition of NH ₄ NO ₂ , NH 4 sulfamate

H ₂ Pt (NO ₂ ) ₂ SO ₄ with addition of H ₂ SO ₄ K ₂ Pt (OH) g with addition of KOH and / or ethylamine H ₂ PtCl 2 in acid baths with HCl addition

Ag: (Ag-110, t ₁ z of ₂ = 250 d) from cyanide baths with KOH

Electrochemical elimination

Stent labeling is accomplished by electrochemical deposition of radioactive metal in accordance with its electrochemical potential relative to the stent metal potential. The deposition is carried out in a suitable electrolyte and under selected reaction conditions. A particularly suitable electrolyte is hydrochloric acid at concentrations of 0.75 N and 1 N. Thus, all radioisotopes of metals whose electrochemical potential is more positive than that of the stent metal can be excluded.

It has been shown that, after electrochemical excretion of radioactive metal, non-specifically bound activity still clings to the stent. To remove this, the stent is treated with a solution containing an electrolyte (e.g. NaCl), a reducing agent and a hydroxycarboxylic acid (e.g. SnCl ₂ and gentisinic acid), or an alcohol and lipophilic cations (e.g. an alcoholic solution of tetrabutylammonium bromide).

The stent thus prepared can then be closed by a polymer. Suitable polymers are, for example, polyacrylate.

· <«· 3 4

4 4 44 4 4 4 4

4 4444

499 44 444 444

4 4 9 4 4 5

4444 4 «444 444 44 44

All stents may also be coated with two or more different isotopes. In particular, it is possible to apply isotopes of short and long lifetime (e.g., ^^ Co with 55p _e , or ^^ Mo with ^{7 7} Co) together on the stent.

It is possible to produce radioactive stents which contain at least one radioisotope of Ag, Au, Bi, Co, Cr, Cu, Fe, Gd, Hg, Ho, In, Ir, Lu, Mn, Ni, Pb on the surface. Pd, Pm, Pt, Re, Rh, Ru, Sc, Roe, Tb, Tc, or Y.

The invention therefore relates to such stents as well as to a process for their production. The operations required to carry out the above-described methods are known to those skilled in the art. Specific embodiments are described in detail in the Examples.

The stents of the invention solve the tasks described at the outset. Stents can be radiolabelled without problems and with accurate dosing. The stents of the invention are physiologically well tolerated. As could be seen in the animal model, after denudation with a balloon, the stent implantation of the invention significantly prevented restenosis.

A particular advantage of the stent of the invention is that the physician can select a (non-radioactive) stent in place according to his needs and then activate the selected stent as described above. The few substances and solutions required for this purpose can be supplied in a pre-prepared manner, so that the physician in question has to immerse the uncoated stent, respectively, in the individual solutions. The invention thus also relates to such substances, solutions and preparations (kits) prepared for the process according to the invention.

· • • • * * * * * * * * * * * *

9 * 9 ** * 9 · * »·

DETAILED DESCRIPTION OF THE INVENTION

The following examples are intended to illustrate the invention without limiting it.

Example 1

Stent Viktor directly marked Y-90.

Stent Viktor (22.85 mg, Modell 6570, Medtronic) was poured over 2 mL of saturated sodium oxalate solution. A solution of 37 MBq of yttrium trichloride-90 was added and heated at 60 ° C for 30 minutes. The stent is then removed and washed 3 times with 5 ml of 0.9% sodium chloride solution. The stent Viktor thus labeled carries an activity of 0.88 MBq of Y-90.

Example 2

Strecker stent coating with Tc-99m

Stent Strecker (6.31 mg, SS / 5-4, Boston Scientific) is poured over 726 μΐ of sodium pertechnetate solution (231.9 MBq). Add 100 μΐ of tin (II) chloride dihydrate solution (5 mg SnCl2H2O / 1 ml 0.01 M HCl), place the reaction mixture in an ultrasonic bath for 5 minutes and then incubate for 25 minutes at room temperature. The stent is dried and washed with 726 μΐ of 0.9% sodium chloride solution 3 times for 15 minutes. Then pour again 726 μΐ of 0.9% sodium chloride solution and stand the reaction mixture! for 5 minutes in an ultrasonic bath. The dried Strecker stent carries an activity of 1.1 MBq-Tc-99m / 6.51 mg (= 29.7 μ € / 6.51 mg = 4.6 μϋϊ / η ^).

:::

• · · · · · · · · · · · · · · · · · ·

Example 3

Coating of a Strecker stent with Re-186

A Stent Strecker (6.60 mg, SS / 5-4, Boston Scientific) was poured over 736 g of sodium perrhenate solution (240.2 MBq). Add 100 μΐ of stannous chloride dihydrate solution (5 mg SnCl.2 H2O / 1 ml 0,01 M HCl), place the reaction mixture in an ultrasonic bath for 5 minutes and then incubate for 25 minutes at + room temperature. The stent is dried and washed 3 times for 15 minutes with 736 μΐ of 0.9% sodium chloride solution. Then pour again over 736 μΐ of a 0.9% sodium chloride solution and place the reaction mixture in an ultrasonic bath for 5 minutes. The dried Strecker stent carries an activity of 1.0 MBq Re-186 / 6.6 mg (= 27 gCi / 6.6 mg = 4.1 gCi / mg).

Example 4

Stent coating by Viktor using Tc-99m

Stent Viktor (22.92 mg, Modell 6570, Medtronic) was poured into 2.56 mL sodium pertechnetate solution (911.5 MBq).

Add 256 μΐ of stannous chloride dihydrate solution (5 mg SnCl2 H2O / 1 ml 0,01 M HCl), place the reaction mixture in an ultrasonic bath for 5 minutes and then incubate for 25 minutes at room temperature. The stent is dried and washed with 2.56 ml of 0.9% sodium chloride solution 3 times for 15 minutes. Then, 2.56 ml of 0.9% sodium chloride solution is poured over and the reaction mixture is placed in an ultrasonic bath for 5 minutes. The dried Viktor stent carries activity of 5.9 MBq-Tc-99m / 22.92 mg (= 159-5 gCi / 22.92 mg = 6.9 gCi / 1 mg).

Fcfc fcfc fcfcfc

Ig * ··· · «··· ···

Example 5

Stent coating with Viktor using Re-186

Stent Viktor (22.31 mg, Modell 6570, Medtronic) was poured over 2.5 ml sodium perrhenate solution (884.1 MBq). 249 μΐ of stannous chloride dihydrate solution (5 mg SnCl ₂ H ₂ 0/1 ml 0,01 M HCl) is added, the reaction mixture is placed in an ultrasonic bath for 5 minutes and then incubated for 25 minutes at room temperature. The stent is dried and washed 3 x 15 minutes with 2.5 ml of 0.9% sodium chloride solution. It is again poured over 2.5 ml of 0.9% sodium chloride solution and the reaction mixture is placed in an ultrasonic bath for 5 minutes. The dried Viktor stent carries an activity of 5.2 MBq-Re-186 / 22.31 mg (= 140.5 gCi / 22.31 mg = 6.3 gCi / 1 mg).

Example 6

Application of Viktor stent, coated with Tc-99m, in abdominal aorta of rabbits

Viktor Stent (Modell 6570, Medtronic) was coated with Tc-99m as described in Example 4. The narcotized (Rompun / Ketavet 1: 2) white New Zealand rabbit (3.2 kg body weight) was exposed to A.femoralis. A labeled Viktor stent was inserted through the 5F plug and inflated into the infrarenal aorta by inflating the balloon catheter. The catheter was then removed and both A. femoralis and wound sutured. At 8 hours after the stent application, whole body scintigrams were made in a conventional gammakamera shop. One scintigram was made 5 hours after the stent application. The activity could only be located in the area of the stent that was in the infrarenal aorta of the animal. Throughout the investigation, • · · 4 * 9 9

444 444 did not flush out any detectable activity from the stent. After 8 hours, the rabbit was sacrificed, the stent was removed, and the activity measured by a gamma counter. The stent- ^{adherent activity was} as high as at the beginning of the experiment with respect to the radioactive decay of? ^9ra Tc to? ⁴ Tc.

Example 7

Labeling a Strecker stent with Cu-67

In a cementation cuvette (Fig. 2a), a Strecker stent (1993 mg) is placed in an alkaline solution of copper sulfate and sodium potassium tartrate having an activity of 67.3 MBq. After addition of the formaldehyde solution, elemental copper is deposited. The active solution is removed and the stent is washed four times with saline. It shows an activity of 1.63 MBq.

CuSO ₄ .5H ₂ 0 KNaC ₄ H ₄ O ₆ .4H ₂ O NaOH 500 mg / 100 ml 2500 mg / 100 ml 700 mg / 100 ml NCOH (38%) 1 ml / 100 ml T Noc: 18 ° C

Example 8

Labeling of Nitinol stent using Au-199

A stent from Nitinol is placed in a cementing cuvette (FIG. 2b) in a solution of potassium and gold cyanide (K [^ Au Au (CN) 4) having an activity of 137.8 MBq, potassium cyanide and potassium hydroxide. After heating to 75 ° C, potassium borane was added and stirred for 3 minutes. After 4 minutes, the solution is drained and the stent is washed four times with saline.

Ftft ftft ft ft

Its activity is 1.31 MBq.

K [Au (CN) ₃ ]

KCN

KOH

KBH,

580 mg / 100 ml 1300 mg / 100 ml 1120 mg / 100 ml 2160 mg / 100 ml

Example 9

Labeling of Strecker stent with Ag-110

A Strecker stent (997 mg) is placed in a cementing cuvette in a solution consisting of sodium cyanide (NaAg (CN) ₂ ) having an activity of 40 MBq / mg stent, sodium cyanide, sodium hydroxide. After heating to 55 ° C, dimethylborane was added. Stir for 4 minutes at 55 ° C, then drain the solution, wash the stent four times with saline and determine

Na [Ag (CN) ₂ ]

NaCN

NaOH

KBHy,

Na [Ag (CN) ₂ ]

It amounts to 1.34 MBq. 183 mg / 100 ml 100 ALIGN! mg / 100 ml 75 mg / 100 ml 200 mg / 100 ml 134 mg AgCN + 49 mg NaCN

Example 10

Labeling of Strecker stent with Pd / P-32

In a cementation cuvette (Fig. 2a), a Strecker stent (1996 mg) was added to a solution of palladium chloride, hydrochloric acid, ammonia and ammonium chloride. The solution has a temperature of 4 ° C. 4 ° C. 4 ° C. 4 ° C. ° C and stirred. 9 mg of sodium hypophosphite monohydrate with an activity of 36.4 MBq is mixed into the solution. A palladium-phosphorus alloy having an activity of 1.31 MBq is deposited on the stent.

PdCl ₂ HCl (38%) NH ₄ OH (28%) nh ₄ Ci 200 mg / 100 ml 0.4 ml / 100 ml 16 ml / 100 ml 2.7 g / 100 ml NaH ₂ PO ₂ .H ₂ 0 1 g / 100ml T High: 55 ° C

g of hypophosphite gave 1 g of Pd alloy with 1.5% P

Example 11

Stainless steel stent marking with Pd / P-32

A stainless steel stent (498 mg) was placed in a cementing cell (Fig. 2b) in a solution of palladium chloride, hydrochloric acid, ammonia and ammonium chloride. The solution is at 55 ° C and stirred. 6 mg of sodium hypophosphite monohydrate having an activity of 37.8 MBq is mixed into the solution. A palladium-phosphorus alloy having an activity of 1.16 MBq is deposited on the stent.

PdCl ₂ 200 mg / 100 ml HCl (38%) 0.4 ml / 100 ml NH ₄ OH (28%) 16 ml / 100 ml nh ₄ ci 2.7 g / 100 ml NaH ₂ PO ₂ .H ₂ O T 1 g / 100ml High: 55 ° C

g of hypophosphite gave 1 g of Pd alloy with 1.5% of Pd.

Example 12

Nitinol stent labeling with Pd / P-32

A nitinol stent (96 mg) was added to a cementing cell (FIG. 2b) into a solution of palladium chloride, hydrochloric acid, ammonia, and ammonium chloride. The solution is at 55 ° C and stirred. 3 mg of sodium hypophosphite monohydrate with an activity of 39.4 MBq are mixed into the solution. A palladium-phosphorus alloy having an activity of 1.37 MBq is deposited on the stent.

PdCl ₂ HCl (38%) 200 mg / 100 ml 0.4 ml / 100 ml NH ₄ OH (28%) 16 ml / 100 ml nh ₄ ci 2.7 g / 100 ml

NaH ₂ PO ₂ .H ₂ 0 1 g / 100ml

T 55 ° C of hypophosphite gave 1 g of Pd alloy with 1.5% P

Example 13

Stainless steel stent marking with P-32

A stainless steel stent (1992 mg) was placed in a galvanizing cuvette (FIG. 1) in a phosphoric acid solution having an activity of 22p4 of 4 MBq, heated to 50 ° C. The stent is wired as an anode and electrolyzed for 2 minutes at 2 V. Then the solution is drained and the stent is rinsed four times with saline and the stent activity is measured. It amounts to 0.93 MBq.

4 4 4

4 4 4

444 444

4444 44 44 «· 3 4

Example 14a

Stent Coating Victor 1- {3-N-} 2-methoxyethyl) octadecylsulfamoyl] -2-hydroxypropyl} -4,7,10-tris- (hydroxycarbonylmethyl) -1,4,7,10-tetraazacyclododecane mg 1- {3- N- (2-methoxyethyl) -octadecylsulfamoyl] -2-hydroxypropyl} -4,7,10-tris- (hydroxycarbonylmethyl) -1,4,7,10-tetraazacyclododecane (produced according to DE 43 43 809.5) is dissolved in 1 ml of ethanol. Stent Viktor (22.82 mg, Modell 6570, Medtronic) was poured over the solution. Then 2 ml of water are added and incubated for 15 minutes in an ultrasonic bath. Stent Viktor is removed and dried.

Example 14b

Marking of Viktor stents coated with 1- {3-N-} 2-methoxyethyl) -octadecylsulfamoyl] -2-hydroxypropyl} -4,7,10-tris- (hydroxycarbonylmethyl) -1,4,7,10-tetraazacyclododecane, using In-111

Stent Viktor, coated according to Example 14a, 1- (3-N-} 2-methoxyethyl) -octadecylsulfamoyl] -2-hydroxypropyl} -4,7,10tris- (hydroxycarbonylmethyl) -1,4,7,10-tetraazacyclododecane (produced according to DE 43 40 809.5) was poured over 2 ml of 0.9% sodium chloride solution. After adding 37 MBq of indium chloride solution, the reaction mixture was placed in an ultrasonic bath for 15 minutes. The stent was removed, washed 3 times with 0.9% sodium chloride solution and dried. The stent Viktor thus labeled carried 1.49 MBq of In-111 activity.

·· 99 * 9 9 9

9 9 ·

999 999 ·

Example 14c

Marking of Viktor stent, coated

1- {3-N-} 2-methoxy-ethyl) -octadecylsulfamoyl] -2-hydroxypropyl} -4,7,10-tris- (hydroxycarbonylmethyl) -1,4,7,10-tetraazacyclododecane, using Y- 90

Viktor Stent, coated according to Example 14a with 1- {3-N -} - 2-methoxyethyl) -octadecylsulfamoyl] -2-hydroxypropyl} -4,7,10-tris- (hydroxycarbonylmethyl) -1,4,7,10-tetraazacyclododecane (produced according to DE 43 40 809.5) is poured over 2 ml of 0.9% sodium chloride solution. After adding 37 MBq of yttrium chloride solution, the reaction mixture is placed in an ultrasonic bath for 15 minutes. The stent is removed, washed 3 times with 9.8% sodium chloride solution and dried. The stent Viktor thus labeled carries an activity of 1.12 MBq of Y-90.

Example 15a

Y-90 complex with 1- {3-N-} 2-methoxyethyl) -octadecylsulfamoyl] -2-hydroxypropyl} -4,7,10-tris- (hydroxycarbonylmethyl) -1,4,7,10-tetraaza-cyclododecane mg 1 - (3-N-} 2-methoxyethyl) -octadecylsulfamoyl] -2-hydroxypropyl} -4,7,10-tris- (hydroxycarbonylmethyl) -1,4,7,10-tetraazacyclododecane (produced according to DE 43 43 809.5) is Dissolve in 1 ml of ethanol. After addition of the 70-yttrium chloride solution of 37 MBq, the reaction mixture was refluxed for 10 minutes. The Y-90 complex solution thus prepared can be used to coat a Viktor stent without further purification.

• ·

Example 15b

Viktor Stent Labeling with Y-90 Complex with 1- (3-N-} 2-methoxyethyl) -octadecylsulfamoyl] -2-hydroxypropyl} -4,7,10tris- (hydroxycarbonylmethyl) -1,4,7,10-tetraazacyclododecane

DO 900 μΐ solution of Y-90 complex with 1- {3-N-} 2-methoxyethyl) -octadecylsulfamoyl] -2-hydroxypropyl} -4,7,10-tris {hydroxycarbonylmethyl} -1,4,7,10 Tetraazacyclododecane prepared according to Example 15a was charged with a Viktor stent (22.89 mg, Modell 6570, Meditronic). After addition of 2 ml of water, the reaction mixture is placed in an ultrasonic bath for 15 minutes. The Viktor stent is then removed and washed 3 times with 5 ml of 0.9% sodium chloride solution. The stent Viktor thus labeled carries an activity of 0.98 MBq of Y-90.

Example 16a

N-N-bisundecyl-diethylene-triamine-pentaacetic acid diamide

3.57 g (10 mmol) of diethylenetriaminepentaacetic acid bisanhydride are suspended together with 4.05 g (40 mmol) of triethylamine in 100 ml of absolute dimethylformamide. A solution of 3.42 g (20 mmol) of undecylamine dissolved in 50 ml of absolute dichloromethane is then added dropwise to the reaction mixture. The reaction mixture was stirred at room temperature for 6 hours, filtered and evaporated under gentle vacuum. The residue is dissolved in DMF (3 * 100 ml) and evaporated under vacuum in each case. The foamed reaction product was poured into 50 ml of absolute diethyl ether and stirred overnight. The product is filtered and dried under gentle vacuum.

Yield:

6.3 g (90%) of white powder te te te te te te te te · · · ··· ··· ·· ·

Elementary analysis:

Calculated: C 61.77 H 9.94 N 10.01 0 18.86 Found: C 61.52 H 9.63 N9.91 0

Example 16b

Stent Coating with Viktor N-N-bisundecyldiethylene-triamine-pentaacetic acid diamide mg of N-N-bisundecyl-diethylene-triamine-pentaacetic acid diamide (prepared according to Example 16a) was dissolved in 1 ml of ethanol. Stent Viktor (22.93 mg, Modell 6570, Meditronic) was poured over the solution thus prepared. Then 2 ml of water are added and incubated for 15 minutes in an ultrasonic bath. Stent Viktor is removed and dried.

Example 16c

Labeling of a Viktor stent coated with N-N-bisundecyl-diethylene-triamine-pentaacetic acid diamide with In-111.

The Viktor stent, coated with N-N-bisundecyl diethylene triamine pentaacetic acid diamide according to Example 16b, was poured over 2 ml of 0.9% sodium chloride solution. After adding 37 MBq of indium chloride solution, the reaction mixture is placed in an ultrasonic bath for 15 minutes. The stent is removed, washed three times with 5 ml of 0.9% sodium chloride solution and dried. The stent Viktor thus labeled has an activir of 1.34 MBq In-111.

Example 16d

Marking of a Victor diamond-coated stent Stent 4 · * 4 4 4 4 4 4 4 4

4 4 4 9 4

44 9 4 4,444 444

4 4 4 9 4 5

4444 44 444 499 44

N-N-bisundecyl-diethylene-triamine-penta-acetic acid, using Y-90

The Viktor stent, coated with N-N-bisundecyl diethylene triamine pentaacetic acid diamide according to Example 16b, was poured over 2 ml of 0.9% sodium chloride solution. After adding 37 MBq of yttrium chloride solution, the reaction mixture is placed in an ultrasonic bath for 15 minutes. The stent is removed, washed three times with 5 ml of 0.9% sodium chloride solution and dried. The stent Viktor thus labeled carries an activir of 1.11 MBq of Y-90.

Example 17a

Y-90 complex with N-N-bisundecyl-diethylenetriamine-penta-acetic acid diamide mg of N-N-bisundecyl-diethylene-triamine-pentaacetic acid diamide (Example 4a) is dissolved in 1 ml of ethanol. After the addition of a solution of 37 MBq of yttrium-90 chloride, the reaction mixture was heated to 60 ° C for 10 minutes. The yttrium-90 complex solution thus prepared can be used to coat a Viktor stent without further purification.

Example 17b

Viktor Y-90 Stent Labeling with Y-90 Complex with N-N-bisundecyl-diethylene-triamine-pentaacetic acid diamide

In a 90 μΐ solution of the Y-90 complex with N-N-bisundecyl-diethylene-triamine-pentaacetic acid diamide prepared according to Example 17a, a Viktor stent (22.87 mg, Modell 6570, Medtronic) was added. After addition of 2 ml of water, the reaction mixture is placed in an ultrasonic bath for 15 minutes. The Viktror stent is then removed and washed 3 times with 5 ml 0.9% sodium chloride solution. Thus

4 * 44

44

4 44 44 4444

4 4444

444 44 444 444

4 4 4 4 4 5

4444 44 444 444 44 44 The labeled stent carries an activity of 0.99 MBq.

Example 18a

N-benzyloxycarbonyl-glycyl-N -undecyl-glycinamide

3.63 g (10 mmol) of N-benzyloxycarbonyl-glycylglycine-N-hydroxysuccinimide ester and 1.71 g (10 mmol) of undecylamine are dissolved in 100 ml of absolute dichloromethane. The mixture was stirred at room temperature for 6 hours. It is then diluted with 100 ml of dichloromethane and the organic phase is washed twice with 50 ml of saturated sodium bicarbonate solution and once with 50 ml of water. It is dried over magnesium sulphate and the solvent is evaporated off under vacuum. The crude product was purified by silica gel chromatography (eluent: dichloromethane / methanol 95: 5).

Yield: 3.8 g (90.6%), white powder

Elementary analysis:

calculated: C 65.84 H 8.89 N 10.01 0 15.25 Found: C 65.71 H 9.02 N 10.10 0

Example 18b

Glycyl-N -undecylglycinamide g of N-benzyloxycarbonyl-glycyl-N -undecyl-glycinamide (Example 18a) was dissolved. in 100 ml of absolute ethanol. After addition of 300 mg of palladium on carbon (10%), it is hydrogenated for 2 hours at room temperature (100 kPa of hydrogen). Filter and evaporate in vacuo. The resulting amine was used for the next reaction without further purification.

9 9999

9

9

9

9999 99

Yield: 1.92 g (94.1%), white foam.

Elementary analysis:

calculated: C 63.12 H 10.95 N 14.72 0 11.21 found: C 63.03 H 11.04 N 14.57 0

Example 18c

N- (S-acetyl-mercaptoacetyl) -glycyl-N-glycinamide

285.4 mg (1 mmol) of glycyl-N-undecylglycinamide (Example 18b) and S-acetyl-mercaptoacetic acid ester with N-hydroxysuccinimide are dissolved together in 20 ml of absolute dichloromethane. The reaction mixture was stirred at room temperature for 6 hours. It is then diluted with 20 ml of dichloromethane and the organic phase is washed twice with half-saturated sodium bicarbonate solution and once with 5 ml of water. It is dried over magnesium sulphate and the solvent is evaporated off under vacuum. The crude product was purified by silica gel chromatography (eluent: dichloromethane / methanol 93: 7).

Yield: 362 mg (90.1%), white powder.

Elementary analysis:

calculated: C 56.83 H 8.79 N 10.46 0 15.94 S 7.98 found: C 56.67 H 8.93 N 10.18 0 7.72

7.72

Example 18d

N- (mercaptoacetyl) -glycyl-N -undecylglycinamide

201 mg of N- (S-acetyl-mercaptoacetyl) -glycyl-N-glycinamide (Example 18c) is dissolved in 15 ml of absolute ethanol. It was saturated with argon and a stream was passed through the solution for 30 minutes

0000 00

000 000

000 00 00 ammonia. It is evaporated and the residue is dissolved in 20 ml of dichloromethane. The organic phase is shaken 1x with a 2% aqueous citric acid solution and dried over anhydrous sodium sulfate. The solvent was evaporated in vacuo and the residue was chromatographed on silica gel (eluent: dichloromethane / methanol 9: 1).

Yield: 153 mg (85.1%), white powder.

Elementary analysis:

calculated: C 56.79 H 9.25 N 11.69 0 13.35 S 8.92 found: C 56.67 H 9.43 N 11.48 0 8.71

Example 18e

Stent Coating Victor Viktor N- (mercaptoacetyl) -glycyl-N -undecylglycinamide mg of N- (mercaptoacetyl) -glycyl-N -undecylglycinamide (Example 18d) was dissolved in 15 mL of absolute ethanol. Stent Viktor (22.89 mg, Modell 6580, Medtronic) was poured over the thus prepared solution. Then 2 ml of water are added and incubated for 15 minutes in an ultrasonic bath. Stent Viktor is removed and dried.

Example 18f

Labeling of a Viktor stent coated with N- (mercaptoacetyl) glycyl-N -undecylglycinamide with Re-186

The Stent Viktor coated with N- (mercaptoacetyl) -glycyl-N-undecylglycinamide according to Example 18e is poured over 2 ml of disodium hydrogen phosphate buffer (0.1 M, pH = 8.5). After addition of the 37 MBq perrhenate solution, the reaction is carried out at room temperature. Add 100 μί of stannous chloride dihydrate solution (5 mg SnCl2-2H20 / l ml 0.1 M HCl) to the batch. The reaction mixture is placed in an ultrasonic bath for 15 minutes. The stent is removed, washed 3 times with 5 ml of 0.9% sodium chloride solution and dried. The labeled stent carries 1.31 MBq Re-186 activity.

Example 18g

Re-186 complex with N- (mercaptoacetyl) -glycyl-N -undecyl-glycinamide mg of N- (mercaptoacetyl) -glycyl-N -undecylglycinamide (Example 18d) is dissolved in 800 μΐ of ethanol. After adding 5 mg of disodium L-tartrate and 50 μΐ of 0.1 M sodium hydrogen phosphate buffer (pH = 8.5), 37 mBq perrhenate and 100 μΐ of stannous chloride dihydrate solution (5 mg SnC ^ · 21 ^ 0/1) are added. ml 0.1M HCl). The reaction mixture was heated to 60 ° C for 5 minutes.

The thus prepared solution of the Re-186 complex with N- (mercaptoacetyl) -glycyl-N -undecyl-glycinamide can be directly used to label a Viktor stent.

Example 18h

Marking of Viktor stent with Re-186 complex with N- (mercaptoacetyl) -glycyl-N -undecyl-glycinamide

Viktor Stent (22.99 mg, Modell 6570, Medtronic) was placed in a 900 μΐ solution of Re-186 complex with N- (mercaptoacetyl) glycyl-N-undecyl-glycinamide prepared in Example 18g.

After addition of 2 ml of water, the reaction mixture is placed in an ultrasonic bath for 15 minutes. The Viktor stent is then removed and washed 3 times with 5 ml of 0.9% sodium chloride solution. The labeled stent carries an activity of 1.13 MBq of Re-186.

* 64 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4

4 4

4 · 4 * 4 44

Example 19

Direct marking of Viktor stent using Y-90

Stent Viktor (22.85 mg, Modell 6570, Medtronic) was poured over 2 mL of saturated sodium oxalate solution. A solution of 37 MBq of Yttrium chloride Y-90 was added and heated to 60 ° C for 30 minutes. The stent is then removed and washed 3 times with 5 ml of 0.9% sodium chloride solution. The stent Viktor thus labeled carries an activity of 0.88 MBq of Y-90.

Example 20

Use of bisdecyloylhydrazino diethylenetriamine pentaacetate to coat a stent.

Example 20a

Production of bisdecyloyhydrazino diethylenetriamine pentaacetate

17.5 g of methyl decanoate are dissolved in 1 liter of absolute ethanol and 350 ml of hydrazine hydrate are added. Heat at reflux for 3 hours and then stir at room temperature overnight. The solution was evaporated to about 300 ml and allowed to stand until the product crystallized. After filtration and drying, 16.6 g (= 94% of theory) of decanoic hydrazide are obtained.

Elementary analysis:

calculated: C 64.5% H 11.9% N 15.0% O 8.6% found: C 65.4% H 11.9% N 14.5% φ ·

3.6 g of diethylenetriaminepentaacetic acid bisanhydride are dissolved in 500 ml of DMF and 4.2 ml of triethylamine and 3.7 g of decanoic acid hydrazide are added under a nitrogen atmosphere. It is stirred at room temperature for 24 hours and then the insoluble matter is filtered off. The solution is concentrated and the oily residue is dissolved in 500 ml of ether. After addition of 500 ml of hexane and stirring again, the product crystallized out. After drying, 7.3 g (= 95% of theory) of bisdecyloylhydrazino-diethylenetriamine pentaacetate are obtained.

Example 20b

Coating a Strecker stent with bisdecyloylhydrazino diethylenetriamine pentaacetate.

mg of bisdecyloylhydrazino-diethylenetriamine pentaacetate was dissolved in 1 ml of methanol and precipitated by addition of 2 ml of hexane. A 0.5 cm Strecker stent (SS / 5-4, Boston Scientific) is immersed in this suspension and incubated by ultrasound for 15 minutes. The stent is then removed and dried. This procedure is repeated five times and then the excess deposited material is removed by washing with saline in an ultrasonic bath.

Example 20c

Labeling of a Strecker stent coated with bisdecyloylhydrazino-diethylene-triamine pentaacetate

The treated stent is immersed in a commercially available radioactive metal solution (In-111, Y-90, 76 MBq) for labeling and incubated in an ultrasonic bath for 15 minutes. Then, fcfcfcfcfc is eluted with saline in an ultrasonic bath. A residual radioactivity of 0.3 MBq remains on the stent.

Example 20d

Strecker Stent Coating with Bisdecyloylhydrazino-diethylene-triamine pentaacetate-labeled mg mg of bisdecyloylhydrazino-diethylene-triamine pentaacetate was dissolved in 1 ml of methanol and labeled with a radioactive metal isotope solution (In-111, Y-9, 74 MBq). A 0.5 cm Strecker stent (SS / 5-4, Boston Scientific) is immersed in this solution and incubated for 15 minutes by ultrasound. The stent is then removed and dried. This operation is repeated 3 times and then the soluble activity is removed by washing with saline in an ultrasonic bath.

A residual activity of 0.1 MBq remains on the stent.

Example 21a

Use of thioacetyl-gly-gly-amidoethyl-PEG methyl ether to coat the stent

Preparation of thioacetyl-gly-gly-amidoethyl-PEG-methyl ether g of an aminoethyl-polyethylene glycol-methyl ether having a molecular weight of about 5000 is stirred at room temperature with 3.6 g of N-benzyloxycarbonyl-glycylglycine-N-hydroxysuccinimide ester (Z-gly-gly- In 100 ml of DMF for 24 hours. The solution was concentrated and the residue was used without further purification.

The residue was dissolved in methanol / water 1: 1, 2 g palladium on charcoal was added and hydrogenated under a hydrogen atmosphere (100 kPa pressure) until it was absorbed by about 230 ml hydrogen. The catalyst was then filtered off and the remaining mixture was purified by gel filtration after concentration. After drying, 49 g (= 96% of theory) of glycylglycylamidoethyl-PEG-methyl ether are obtained.

This product was dissolved in DMF (100 mL) and stirred at room temperature with 2.2 g of S-acetyl-thioglycolic ester and N-hydroxysuccinimide for 24 hours. Then 20 ml of aqueous ammonia solution were added to the mixture and stirred for 2 hours. The product was acidified to pH 4 with aqueous 6 N hydrochloric acid and concentrated. Purify through a gel filtration column. 42 g (= 85% of theory) of thioacetyl glycyl-glycyl-amidoethylpolyethylene glycol methyl ester are obtained.

Example 21b

Strecker stent coating with thioacetyl-glycyl-glycyl-amidoethyl-polyethylene glycol-methyl ether and subsequent radio-labeling of mg of thioacetyl-glycyl-glycyl-amido-ethyl-polyethylene glycol-methyl ether with a molecular weight of about 5300 is dissolved in 3 ml of methanol, precipitated with hexane a 0.5 cm Strecker stent (SS / 5-4, Boston Scientific) is immersed in this suspension and incubated for 15 minutes by ultrasound. The stent is then removed and dried. This operation is repeated 5 times and then the excess coating material is removed by washing with physiological saline solution in an ultrasonic bath.

The treated stent is immersed in a solution of radioactive metal isotope (Tc-99m, Re-186) consisting of 5 ml solution (Tc-99m from the generator, Re-186 from the store, contains about 3 MBq activity), 200 μΐ phosphate buffer (Na ₂ HPO ₄ , 0.5 mol / l, pH · 9 · fr · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ··· · · · · · · ······ · 9 ··· ··· ·· ··

8.5), 50 μl of 0.15 molar solution of disodium tartrate as well as 2.5 μί of 0.2 molar SnCl ₂ solution and incubated for 15 minutes in an ultrasonic bath. It is then washed for 20 minutes in saline in an ultrasonic bath. A residual activity of 0.1 MBq remains on the stent.

Example 21c

Strecker Stent Coating with radiolabeled thioacetyl-glycyl-glycyl-amidoethyl-polyethylene glycol-methyl ether

0.5 mg of thioacetyl-glycyl-glycyl-amido-ethyl-polyethylene glycol-methyl ether with a molecular weight of about 5300 is dissolved in 300 μΐ of phosphate buffer (Na 2 PO 4, 0,5 mol / l, pH 8,5) and added 50 ml of a 0,15 molar solution of disodium tartrate and 2,5 μΐ of a 0,2 molar SnCl ₂ solution. Pertechnate solution (5 MBq) from the Tc-99m generator was added to the mixture and incubated for 15 minutes at 60 ° C. Similarly, a solution of polyethylene glycols labeled with Re-186 may be prepared. A 0.5 cm Strecker stent (SS / 5-4, Boston Scientific) was immersed in this solution and incubated for 15 minutes by ultrasound. The stent is then removed and dried. This operation is repeated several times until the adhered activity is 0.3 MBq. It is then washed twice with physiological saline for 60 minutes. A residual activity of 100 kBq remains.

Example 22

Strecker Stent Coating with TC-99m-Asp-Gly-Gly-Cys-Gly-Cys-Phe- (Dr-Trp) -Leu-Asp-Ile-Ile-Trp

0.5 mg of Asp-Gly-Gly-Cys-Gly-Cys-Phe- (Dr-Trp) -Leu-AspIle-Ile-Trp, prepared according to Barany and Marfield, The Peptide37 des; Analysis, Biology, Academic Press, New York 1990, Stewart and Young, Solid Phase Peptides Synthesis, 2 ^nt . Pierce Chemical Co. Rockford, IL, 1984, was dissolved in 300 mL of phosphate buffer (Na ₂ HPO ₄ , 0.5 mol / l, pH 8.5) and 50 µΐ of a 0.15 molar solution of sodium L-tartrate was added as well as 2 , 5 μΐ 0,2 molar stannous chloride dihydrate solution. Pertechnate solution (50 mCi = 1.85 GBq) from the Mo-99 / Tc-99m generator was added and incubated for 10 minutes at room temperature.

The Strecker stent (SS / 5-4, Boston Scientific) was sequentially incubated five times for 15 minutes each in a Tc-99m-peptide solution.

After each incubation, the activity adhered to the stent is determined using a conventional gamma counter. As shown in the figure, after a single incubation, a Strecker stent adheres to 230 μ ^.

Repetition of this incubation no longer results in any appreciably higher activity adhering to the stent. Then, the stent, coated with the Tc-99M-peptide solution, is washed four times for one minute and twice for 60 minutes in physiological saline. After the first rinse, 81 pCi remained on the stent. Further rinsing does not result in a significant reduction in stent-retained activity.

Example 23

Stent coating by Viktor using Tc-99m

Stent Viktor (22.92 mg, Modell 6570, Medtronic) was poured into 2.56 mL sodium pertechnetate solution (911.5 MBq). To this is added 256 µl of tin (II) chloride dihydrate solution (5 mg SnCl _2. 2H ₂ 0/1 ml 0.01 M HCl), the reaction mixture is placed in an ultrasonic bath for 5 minutes and then incubated for 25 minutes at room temperature. The stent is dried and washed 3 times for 15 minutes with 2.56 ml of 0.9% sodium chloride solution. Then, 2.56 ml of 0.9% sodium chloride solution is poured over and the reaction mixture is placed in an ultrasonic bath for 5 minutes. Dried Viktor stent carries activity of 5.9 MBq-Tc-99m / 22.92 mg (= 159.5 gCi / 22.92 mg =

6.9 pCi / 1 mg).

Example 24

Stent coating with Viktor using Re-186

Stent Viktor (22.31 mg, Modell 6570, Medtronic) was poured into 2.56 mL sodium perrhenate solution (884.1 MBq). To this is added 249 μί of stannous chloride dihydrate solution (5 mg SnCl ₂ · 2H ₂ 0/1 ml 0.01 M HCl), the reaction mixture is placed in an ultrasonic bath for 5 minutes and then incubated for 25 minutes at room temperature. The stent is dried and washed 3 times for 15 minutes with 2.5 ml 0.9% sodium chloride solution. It is again poured over 2.5 ml of 0.9% sodium chloride solution and the reaction mixture is placed in an ultrasonic bath for 5 minutes. Dried Viktor stent carries activity of 5.2 MBq-Re-186 / 22.31 mg (= 140.5 pCi / 22.31 mg =

6.3 pCi / 1 mg).

Example 25

Application of Viktor stent, coated with Tc-99m, in abdominal aorta of rabbit

Viktor Stent (Modell 6570, Medtronic) was coated with Tc-99m as described in Example 10. The narcotized (Rompun / Ketavet 1: 2) white New Zealand rabbit (3.2 kg body weight) was exposed to A-femoralis. A labeled Viktor stent was inserted through the F5 cap and inflated into the infrarenal aorta by inflating the balloon catheter. Then the catheter was removed and both A.femoralic and suture were sewn. At the time • 9 9

9 · 9

9 9 9 9 9

* 9 hours after stent application, whole body scintigrams were taken to assist in the usual gammakamera shop. Figure XI shows a scintigram taken 5 hours after stent application. The activity could only be located in the area of the stent that was in the infrarenal aorta of the animal. No detectable activity was flushed from the stent throughout the investigation. After 8 hours, the rabbit was sacrificed, the stent was removed, and the activity measured by a gamma counter. The stent-retained activity was as high as at the beginning of the experiment.

Example 26a

Cementation of Stercker gold stent

The Strecker stent (about 200 mg) was coated with gold in a cementing cuvette (Figure 2a) (30 min of gold chloride in 5% aqueous hydrochloric acid for 2 minutes). The stent thus obtained is washed three times with 10% nitric acid and twice with water. Then twice with acetonitrile and dried.

Example 26b

Binding of 11-amino-undecyl-1-thiol to the surface

500 mg of 11-amino-undecyl-1-thiol are dissolved in a solution of 10 ml of 7.5% aqueous nitric acid / 5 ml of tetrahydrofuran / 3 ml of 1,2-dichloromethane. A Strecker stent prepared in Example 26a is immersed in a shielding gas (in an ultrasonic bath at 37 ° C) under this shielding gas.

• · · · ·

Example 26c

Coupling with DTPA-bis-anhydride

The stent described in Example 26b is immersed in a 7.5% aqueous solution of sodium carbonate and 500 mg of DTPA-bis-anhydride are added in portions of 100 mg with stirring at 0 ° C. Stir 10 minutes at 0 ° C. The stent was washed twice with 5% aqueous hydrochloric acid, then three times with water and twice with acetonitrile.

Example 26d

Labeling of DTPA-amide-treated stent indium-111

The stent described in Example 26c is immersed in an acetate buffer solution (0.001 mol, pH 5.5) and an In-111 solution (starting activity: 48.8 MBq) is added. Stir 5 minutes at room temperature. The stent is washed three times with 3% aqueous sodium carbonate solution, then twice with physiological common salt solution. The stent can be used immediately for implantation.

The stent has a radioactivity level of 1.2 MBq.

Example 27a

DOTA Binding to the Stent of Example 26b

The stent obtained in Example 26b is immersed in phosphate buffer (0.1 ml / l, pH 7.4) and 150 mg of 1,4,7,10-tetraazacyclodecane (DOTA) is added. Cool to 0 ° C and add 200 mg of N-hydroxysulfosuccinimide (sulfo-NHS) with 200 mg of 1-ethyl-3- (dimethylaminopropyl) carbodiimide.HCl (EDC). Stir 30 minutes at 0 ° C. The stent is washed twice with water, twice with physiology41

444 444

4 with table salt solution.

Example 27b

Tagging with In-111

The stent described in Example 27a is immersed in an acetate buffer solution (0.01 ml, pH 5) and an In-111 solution (starting activity: 37.3 MBq) is added, heated to 50 ° C for 30 minutes. was washed twice with 3% aqueous sodium carbonate, then three times with brine. The stent has an activity of 1.45 MBq.

Example 28a

Binding of 4-isothiocyanato-benzyl-DTPA to the stent of Example 26b

The stent prepared according to Example 26b was immersed in a solution of sodium carbonate buffer (0.1 mol / l, pH 9) and 100 mg of 4-isothiocyanato-benzyl DTPA (Gansow, 0.V) was added.

91/14459). Stir 30 minutes at room temperature. The stent is washed twice with 3% sodium carbonate solution, then three times with physiological saline solution.

Example 28b

Marking by Cu-67

The stent described in Example 28a is immersed in acetate buffer (0.01 mol, pH 5) and Cu-67 solution (starting activity 34.5 MBq) is added. Stir 5 minutes at room temperature. The stent is washed twice with 3% aqueous sodium carbonate solution, then three times with physiological saline solution. Stent shows

0 «to 0 0 0 to 0 0 0

000 000

0 · 0 0

0 radioactivity 0.98 MBq.

Example 29a

Binding of 4-isothiocyanato-benzyl-DTA to the stent of Example 26b

The stent prepared according to Example 26b is immersed in a solution of sodium carbonate buffer (0.1 ml / l, pH 9) and 100 mg of 4-isothiocyanato-benzyl DOTA (Gansov, O., US 4,923,985) is added. Stir 30 minutes at room temperature. The stent is washed twice with 3% sodium carbonate solution, then three times with physiological saline solution.

Example 29b

Marking Cu-67

The stent described in Example 29a is immersed in acetate buffer (0.01 mol, pH 5) and Cu-67 solution (starting activity 28.6 MBq) is added. Stir 15 minutes at 40 ° C. The stent is washed twice with 3% sodium carbonate solution, then three times with physiological saline solution. The stent exhibits a radioactivity of 0.77 MBq.

Example 30a

Cystamine bisamide with DTPA g (28 mmol) of DTPA-bis-anhydride was suspended in 100 ml of dimethyl sulfoxide. Cool to 0 ° C and add 5.7 g (56 mmol) of triethylamine. Then, 1.58 g (7 mmol) of cystamine dihydrochloride are added and stirred at room temperature for 24 hours. 20 ml of formic acid and 1000 ml of diethyl ether are added.

• 4 • 4 • 4

4 * 1 · 4 4 4

4 4 4 hylether. The precipitated solid is filtered off and chromatographed on RP18 (mobile phase: gradient from acetonitrile / THF / water). The product obtained after evaporation of the main fractions was recrystallized from a little methanol.

Yield: 1.96 g (31% of theory, based on cystamine), colorless hygroscopic solid.

Water content: 6.8%

Elemental analysis (calculated on the anhydrous basis) Calculated: C 42.57 H 6.03 N 12.41 S 7.10 Found: C 42.39 H 5.97 N 12.53 S 7.03

Example 30b

Binding of DTPA-cystaminamide to Strecker stent, gold cemented (26a)

The Strecker stent described in Example 26a is mounted in an electrolytic cuvette (Figure 1) and a phosphate buffer solution (0.1 mol / L, pH 5) is added. 100 mg of the title compound of Example 126a was added to the solution and a voltage of 3 V was applied. Electrolyzed at room temperature for 15 minutes. The stent is washed four times with water and can be used directly for labeling.

Example 30c

Tagging with In-111

The stent described in Example 30b is immersed in an acetate buffer solution (0.01 mol, pH 5) and an In-111 solution (starting activity: 24.7 MBq) is added. Stir 5 minutes at room temperature. The stent is washed twice with a 3% aqueous solution of carbon. The stent is washed twice with a 3% aqueous solution of carbon. tetanus sodium, then three times with saline. The stent has a radioactivity of 1.11 MBq.

Example 31

Tagging Cu-67

The stent described in Example 30b is immersed. into assetate buffer (0.01 mol, pH 5) and Cu-67 solution (starting activity: 41.2 MBq) is added. Stir 3 minutes at room temperature. The stent is washed twice with 3% aqueous sodium carbonate solution, then three times with physiological saline solution. The stent has a radioactivity of 0.97 MBq.

Example 32a

Binding of N, N-dimethyl-2- (3,3,5,11,13,13-hexamethyl-1,2-dithia5,8,11-triaza-cyclotridecan-8-yl) -ethylamine to a Strecker stent, cemented with gold

The Strecker stent described in Example 26a is mounted in an electrolytic cuvette (Figure 1) and a phosphate buffer solution (0.1 mol / L, pH 5) is added. To the solution is added N, N-dimethyl-2- (3,3,5,11,13,13-hexamethyl-1,2-dithia-5,8,11-triaza-cyclotridecan-8-yl) -ethylamine (produced according to WO 96) (11918, Example 27), and a voltage of 3.5 V was applied. Electrolyzed for 15 minutes at room temperature. The stent is washed four times with water and can be used directly for labeling.

Example 32b

Marking with Re-186 • to * ·· this

The stent described in Example 32a is immersed in a solution consisting of 30 ml acetate buffer (0.01 mol, pH 5 and 100 mg stannous chloride) and Re-186 solution (starting activity:

48.3 MBq). Stir 3 minutes at room temperature. The stent is washed twice with 3% aqueous sodium carbonate solution, then three times with physiological saline solution. The stent has a radioactivity of 1.44 MBq.

Example 33

Labeling a gold-cemented stent with In-111 in the in-sieve binding of the title compound of Example 30a by electrochemical reaction.

The Strecker stent described in Example 26a is mounted in an electrolyte rocker (Figure 1) and phosphate buffer solution (0.1 mol / l, pH 5) is added. To the solution is added 10 mg of the title compound of Example 30a, In- 111 (default activity: 34.6 MBq) and attach! se napět! Electrolyzed at room temperature for 15 minutes. The stent is washed twice with a 3% aqueous sodium carbonate solution, then twice with water and can be directly implanted. The stent exhibits a radioactivity of 0.77 MBq.

Example 34

Labeling of a gold-cemented stent with Cu-67 in the in-situ binding of the title compound of Example 30a by electrochemical reaction.

The Strecker stent described in Example 26a is mounted in an electrolytic rocker (Figure 1) and citric acid buffer solution (0.1 mol / l, pH 5) is added. To the solution is added 10 mg of the title compound of Example 30a, solution Cu-67 (app. 46 • 9 9999)

99 µl activity: 36.7 MBq) and a voltage of 1.8 V is applied. Electrolysis is carried out for 15 minutes at room temperature. The stent is washed twice with a 3% aqueous sodium carbonate solution, then twice with water and can be directly implanted. The stent has a radioactivity of 0.98 MBq.

Example 35

S-35 aid tagging

The stent produced according to Example 26a was immersed in a solution of 5% aqueous hydrochloric acid and a cysteine solution with S-35 (starting activity: 37.5 MBq) was added. Stir 5 minutes at room temperature. The stent is washed four times with saline. Radioactivity was measured

1.35 MBq.

Example 36

Labeling of Strecker stent with Cu-67

The Strecker stent (93 mg) was mounted in an electrolytic cuvette as described in Figure 1. Then the cuvette was filled with 5% aqueous hydrochloric acid and Cu-67 solution (starting activity 47.4 MBq) was added. A voltage of 2 V is then applied. It is electrolyzed at room temperature for 5 minutes. The radioactive solution is discharged through a valve and the stent is washed four times with saline. The surface-labeled Strecker stent contains 1.56 MBq of radioactivity and can be used directly as an implant.

• 9 9 a 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9

Example 37

Labeling of Nitinol stent with Cu-67

Stent Nitinol (about 500 mg) is labeled in a similar manner to that described in Example 1. However, it is electrolyzed for 10 minutes at a voltage of 1.5 V. The stent exhibits a radioactivity of 3.21 MBq.

Example 38

Labeling of Nitinol stent with Re-186

The nitinol stent (about 1000 mg) is mounted in the electrolytic cuvette described in Figure 1. Phosphate buffer (0.01 mol / l, pH 5) is then added. Re-186 solution (starting activity 51.4 MBq) was then added and a voltage of 2.5 V was applied. The radioactive solution was removed and the stent was washed four times with saline. The stent has a radioactivity of 2.44 MBq.

Example 39

Marking of Palmaz-Schatz (stainless steel 316) stent with Re-186

The Palmaz stent (about 200 mg) is mounted in an electrolytic cuvette (Fig. 1) and a 5% nitric acid solution in which 150 mg of sodium chloride is dissolved is added. Add Re-186 solution (starting activity 37.4 MBq) and apply voltage

Electrolyzed at room temperature for 5 minutes. Remove the radioactive solution and wash the stent four times with saline. The stent has a radioactivity of 1.98 MBq.

• · ·

«·

9 »9 · 99

Λ

9 9

Example 40

Labeling of Strecker stent using Au-199

The Strecker stent (about 150 mg) was mounted in an electrolytic cuvette (Fig. 1) and a 7.5% aqueous hydrochloric acid solution was added. Au-199 solution is then added (starting activity:

45.2 MBq) and attach! Electrolysis was carried out at room temperature for 5 minutes. Remove the radioactive solution and wash the stent four times with saline. The stent has a radioactivity of 2.13 MBq.

Example 41

Marking of Strecker Au-199 stent

The Strecker stent (about 350 mg) was mounted in an electrolytic cuvette (Figure 1) and a 2.5% aqueous hydrochloric acid solution was added in which 100 mg tetramethylammonium chloride / ml was dissolved. Au-199 solution is then added (starting activity:

55.6 MBq) and applied at a voltage of 1.2 V. It was electrolyzed for 4 minutes at room temperature. Remove the radioactive solution and wash the stent four times with saline. The stent has a radioactivity of 1.81 MBq.

Example 42

Marking of stent Z (304 stainless steel) using Au-199

Stent Z (about 250 Mg) is mounted in an electrolytic cell (Fig. 1) and a 2.5% aqueous hydrochloric acid solution is added in which 100 mg of tetramethylammonium chloride is dissolved. 99 9 9 «Du / ml. Au-199 solution is then added (starting activity:

38.6 MBq) and applied at a voltage of 1.2 V. Electrolyzed at room temperature for 3 minutes. Remove the radioactive solution and wash the stent four times with saline. The stent has a radioactivity of 1.13 MBq.

Example 43

Marking of stent Z (304 stainless steel) with Ag-110

Stent Z (about 250 mg) was mounted in an electrolytic cuvette (Fig. 1) and a 5% aqueous nitric acid solution in which 100 mg tetramethylammonium chloride / ml was dissolved. Ag-110 solution (starting activity: 56.8 MBq) was then added and 1.5 volts applied. Electrolyzed at room temperature for 2 minutes. Remove the radioactive solution and wash the stent four times with saline. The stent has a radioactivity of 1.54 MBq.

Example 44

Marking of Nitinol stent (stainless steel 304) with Ag-110

The nitinol stent (about 1500 mg) was mounted in an electrolytic cuvette (Fig. 1) and a 7.5% aqueous nitric acid solution in which 150 mg tetramethylammonium chloride / ml was dissolved. Ag-110 solution (starting activity:

39.4 MBq) and a voltage of 1.4 V is applied. Electrolyzed at room temperature for 10 minutes. The radioactive solution is removed and the stent is washed four times with water and twice with saline. The stent has a radioactivity of 1.78 MBq.

Example 45

Labeling of the Nitinol stent with In-111

The nitinol stent (about 1500 mg) is mounted in an electrolytic cuvette (Fig. 1) and a 5% aqueous citric acid solution in which 150 mg tetramethylammonium chloride / ml is dissolved. Then, the In-111 solution (starting activity:

51.3 MBq) and apply voltage! Electrolyzed at room temperature for 7 minutes. The radioactive solution is removed and the stent is washed twice with water and twice with brine. The stent has a radioactivity of 1.45 MBq.

Example 46

Marking of stent Z with In-111

Stent Z (about 500 mg) is mounted in an electrolytic cuvette (Fig. 1) and a 5% aqueous citric acid solution in which 150 mg tetramethylammonium chloride / ml is dissolved. The In-111 solution (starting activity: 36.9 MBq) was then added and a voltage of 3.8 V was applied. The radioactive solution is removed and the stent is washed twice with water and twice with brine. The stent has a radioactivity of 1.77 MBq.

Example 47

Labeling of Strecker stent using Au-199

Insert a Strecker stent into the cementing vessel (Fig. 2b).

9 9 ·· ·

(about 93 mg) with aqueous hydrochloric acid (pH 3). Add Au-199 chloride solution (starting activity:

32.6 MBq) and stirred at room temperature for 10 minutes. The stent is washed four times with saline and can be used directly for implantation. The stent has a radioactivity of 1.22 MBq.

Example 48

Labeling of Strecker stent with Ag-110

A Strecker stent (about 496 mg) with an aqueous solution of nitric acid (pH 4) is placed in a cementing vessel (Fig. 2a). Add Ag-110 nitrate solution (starting activity: 37.6 MBq) and stir for 10 minutes at room temperature. The stent is washed four times with dilute nitric acid (pH 3), twice with water and can be used directly for implantation. The stent has a radioactivity of 1.02 MBq.

Example 49

Marking of stent Z using Au-199

A stent Z (about 987 mg) with an aqueous hydrochloric acid solution (pH 3) was placed in a cementing vessel (Fig. 2a). Add Au-199 chloride solution (starting activity:

41.5 MBq) and stirred at room temperature for 10 minutes. The stent is washed four times with saline and can be directly used for implantation. The stent has a radioactivity of 1.16 MBq.

• a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a

Example 50

Marking of Nitinol stents using Au-199

Place a Nitinol stent (about 483 mg) with an aqueous hydrochloric acid solution (pH 3) into a cementing vessel (Fig. 2b). Add Au-199 chloride solution (starting activity:

39.7 MBq) and stirred at room temperature for 10 minutes. The stent is washed four times with saline and can be directly used for implantation. The stent has a radioactivity of 0.98 MBq.

Example 51

Marking of Strecker stents using Re-186

The Strecker stent was placed in an electrolytic cell (Figure 1) and a solution of zinc sulfate acidified with sulfuric acid (50 mg / ml, pH 5) was added. After insertion of the zinc anode, it is electrolyzed for 10 minutes at 1.5 volts. The stent thus galvanized is washed four times with water. A stent with an aqueous citric acid solution (pH 5) is placed in a cementing vessel (Fig. 2a). Add Re-186 solution (starting activity: 41.6 MBq) and stir for 10 minutes at room temperature. The stent is washed four times with saline and can be directly used for implantation. The stent has a radioactivity of 1.31 MBq.

Example 52

Marking of stents Z (304 stainless steel) Re-186

The Stent Strecker is placed in an electrolytic cuvette.

(Fig. 1) and a solution of stannous chloride acidified with hydrochloric acid (50 mg / ml, pH 5) is added. After insertion of the tin anode and electrolysis for 5 minutes at a voltage of 3 volts. The above stent with an aqueous citric acid solution (pH 5) is placed in a cementing vessel (Fig. 2a). Add Re-186 solution (starting activity: 37.7 MBq) and stir for 10 minutes at room temperature. The stent is washed four times with saline and can be directly used for implantation. The stent has a radioactivity of 1.44 MBq.

Example 53

Labeling of Nitinol stent with Cu-67

A nitinol stent (about 488 mg) with an aqueous hydrochloric acid solution (pH 3) was charged into the cementation vessel (Fig. 2b). Add Cu-67 sulfate solution (starting activity:

24.6 MBq) and stirred at room temperature for 10 minutes. The stent is washed four times with saline and can be directly used for implantation. The stent has a radioactivity of 1.55 MBq.

Example 54

Marking of Palmaz stent (316 stainless steel) using Cu-67

A Palmaz stent (about 977 mg) with an aqueous hydrochloric acid solution (pH 3) was charged into the cementation vessel (Fig. 2a). Add Cu-67 sulfate solution (starting activity:

24.6 MBq) and stirred at room temperature for 10 minutes. The stent is washed four times with saline and can be directly used for implantation. The stent shows radioactivity.

0.88 MBq.

Example 55

Marking of Palmaz stent (316 stainless steel) with Re-186

Place a Palmaz stent in an electrolysis cell (Figure 1) and add a solution of stannous chloride acidified with hydrochloric acid (50 mg / ml, pH 5). After insertion of the tin anode, it is electrolyzed at 5 volts for 5 minutes. The tinned stent is washed four times with water. The above-described stent is placed in a cementation vessel (Fig. 2a) with an aqueous citric acid solution (pH 5). Add Re-186 solution (starting activity: 34.5 MBq) and stir for 10 minutes at room temperature. The stent is washed four times with saline and can be directly used for implantation. The stent has a radioactivity of 1.98 MBq.

Example 56

Marking of Palmaz stent (316 stainless steel) with Ag-110

A Palmaz stent (about 977 mg) with an aqueous solution of nitric acid (pH 4) is placed in a cementing vessel (Fig. 2a). Add Ag-110 sulfate solution (starting activity: 24.6 MBq) and stir for 10 minutes at room temperature. The stent is washed four times with water and can be used directly for implantation. The stent exhibits a radioactivity of 1.12 MBq.

0 · 0 • 0 • 0 00

0 0 0

000 000

0

0 0 0

Example 57

Pour the Palmaz stent (15 mm, 80.3 mg, Johnson and Johnson) with 1.0 ml of a marker solution consisting of 173 μΐ sodium perrhenate solution (164 MBq) and 827 μΐ IN HCl. The reaction vessel is placed in an ultrasonic bath (ultrasonic power 80%) for 60 minutes at 50 ° C. The stent is then removed, rinsed with distilled water and dried. The dried stent carries an activity of 36.2 MBq = 0.45 MBq / mg stent. To remove non-specifically bound activities, the stent is incubated for 60 minutes in 1 ml 0.9% NaCl solution at 37 ° C. After drying, the stent still carries activity

9.7 MBq = 0.12 MBq / mg stent.

Example 58

Pour the Palmaz stent (1/11 stent = 26.2 mg, Johnson and Johnson) with 1.5 ml of a marking solution consisting of 60 μΐ perrhenate solution (60 MBq) and 1440 μΐ 1 N HCl. The reaction vessel was sealed and heated to 100 ° C (boiling water bath) for 30 minutes. The stent is then removed, rinsed with distilled water and dried. The dried stent carries an activity of 25.9 MBq (0.98 MBq / mg stent). To remove or fix non-specifically bound activities, the stent is incubated for 10 minutes in 2 ml of 0.1 M gentisic acid / 0.1 M SnCl ₂ solution with shaking. After drying, the stent carries an activity of 16.1 MBq (0.61 MBq / mg stent).

Example 59

Pour the Palmaz stent (31.4 mg, Johnson and Johnson) with 1.5 ml of a marker solution consisting of 60 μΐ sodium perrhenate solution (81 MBq) and 1440 μΐ 0.75 N HCl. The reaction vessel was sealed and heated to 100 ° C (boiling water bath) for 30 minutes. Then the stent is removed, rinsed with distilled water

4 • 4 4

4 »4 4 4 and dried. The dried stent is fixed at 27.1 MBq (0.86 MBq / mg stent). To remove non-specifically bound activities, the stent is incubated for 10 minutes in 2 ml of 0.1 M tetrabutylammonium bromide solution with shaking. After drying, 17.0 MBq (0.54 MBq / mg of stent) is fixed to the stent.

Example 60

The stent of Example 59 is immersed several times in a solution of 16% vinyl acetate polymer and acrylate in ethyl acetate after drying at room temperature. After drying, the stent is ready for use.

· Φ φ • • · · · · · · · · · · · · ·

List of reference marks

Cover

Partition

Partition

Cuvette (teflon or glass)

Stent

6. Solution (+) Pt anode, ring anode

Magnetic stirrer bar (-) Pt cathode

Shut-off valve

Two-way valve

Magnetic stirrer

Rinse liquid

Active solution

Adding solutions: Syringe or dosing pump

When adding by syringe: Put the Septa into the lid

When electrolysed at elevated temperature, the solution is preheated.

Claims (25)

A method for producing radioactive stents, characterized in that the non-radioactive stent is immersed in a solution containing at least one radioactive isotope, and the isotope is then chemically deposited on the stent. 2. The method of claim 1 wherein the isotope on the stent is reduced by reduction. Process for the production of radioactive stents according to claim 2, characterized in that SnCl ₂ , KBH ₄ , dimethylborane, formaldehyde or sodium hypophosphite is used as reducing agent. A method for producing radioactive stents according to claim 1, characterized in that the isotope on the stent is eliminated by chemical precipitation. Process for the production of radioactive stents according to claim 4, characterized in that oxalic acid, oxalates, phosphoric acid, phosphates or Na ₂ CO ₂ are used as precipitants. Method for the production of radioactive stents according to one of claims 1 to 5, characterized in that the radioactive isotope is an isotope of Ag, Au, Co, Cr, Cu, Fe, Gd, Hg, Ho, In, Ir, Lu, Mn, Ni, P, Pd, Pd, Pm, Ρΐ, Re, Rh, Ru, Sc, Srn, Tb, Tc, or Y. • · ·· · · 9 9 9 99 9 9 9 9 9 9 9 9 99,999 9 9 9 9 99 The method of producing radioactive stents by chemical precipitation according to claim 4, characterized in that the metal surface of the stent is anodically oxidized in a solution of radioactive phosphoric acid. A process for the production of radioactive stents according to any one of claims 1 to 7, characterized in that a plurality of isotopes are deposited on the stent surface. Use of radioactive stents which have been produced by any of the methods of claims 1 to 8 for the manufacture of an implant for the prophylaxis of restenosis. 10. Radioactive stents, characterized in that the radioactive isotope is fixed on the surface of the stent by means of at least one adhesion promoter. 11. Radioactive stents, characterized in that at least one radioactive isotope of the elements Ag, Au, Ba, Bi, C, Co, Cr, Cu, Fe, Gd, Hg, Ho, In, Ir, Lu, Mn, Ni, P , Pb, Pd, Pm, Pt, Re, Rh, Ru, Sc, Srn, Tb, Tc, or Y is fixed to the stent surface by at least one adhesion promoter. Radioactive stents according to claim 10 or 11, characterized in that the adhesion promoter is a peptide, fat or gold in combination with a thiol-group-containing complexing agent. • 9,999 9 »· · ·· ·« Radioactive stents according to claim 10 or 11, characterized in that the adhesion promoter is composed of a complexing peptide, a complexing fat or gold in combination with a complexing agent containing a thiol group. Radioactive stents according to claim 10, characterized in that the radioactive isotope is an isotope of Ag, Au, Ba, Bi, C, Co, Cr, Cu, Fe, Gd, Hg, Ho, In, Ir, Lu, Mn, Ni, P, Pd, Pd, Pm, Pt, Re, Rh, Ru, Sc, Srn, Tb, Tc, or Y. 15. A process for the manufacture of radioactive stents, characterized in that, at 0 to 100 [deg.] C., the adhesion promoter is reacted with a radioactive isotope and the stent is then coated at 0 to 100 [deg.] C. with a radiolabelled promoter. 16. A process for the manufacture of radioactive stents, characterized in that the non-radioactive stent at 0 to 100 [deg.] C. is coated with a sticky agent and then reacts at 0 to 100 [deg.] C. with a radioactive isotope solution. 17. A method for producing radioactive stents, characterized in that the non-radioactive stent is coated with gold and then reacted with a solution of a thiol compound labeled with S. Use of a stent, consisting of a stent body, an adhesion promoter and a radioactive isotope, in the manufacture of an implant for the prophylaxis of restenosis. ···························· 19. A process for the production of radioactive stents, characterized in that the non-radioactive stent is immersed in a solution containing the readioactive isotope in ionic form and that the isotope is then precipitated electrochemically on the stent. A method for producing radioactive stents according to claim 19, characterized by and s e t í m that is isotope on stent excluded galvanic. 21. Method of production of radioactive stents according to claim 19, v y z n and c and s e t i m that is isotope on stent excluded cementation. 22nd Method according to at least one from claims 19 to 21, v y z n and c and s e t i m that radioactive izoto pem j e isotope elements Ag, Au, Bi, C, Co, Cr, Cu, Fe, Gd, Hg, Ho, In, Ir, Lu, Mn Ni, Pb, Pd, Pm, Pt, Re, Rh, Ru , Se , Sm, Tb, Tc, or Y. A method for producing a radioactive stent according to claim 1 or 19, characterized in that the solution containing the radioactive isotope in ionic form additionally contains hydrochloric acid. 24. A method for producing radioactive stents according to claim 1 or 19, wherein the stent is treated with a solution comprising a reducing agent and hydroxycarboxylic acid in a further step of the process. • 4 ·· 4 4 4 4 4 4 444 444 • 4 4 444 44 ·· 25. A process for the production of radioactive stents according to claim 1 or 19, characterized in that the stent is treated with a solution containing alcohols and lipophilic cations in a further process step. A method for producing radioactive stents according to claim 23, 24 or 25, characterized in that the stent is additionally sealed with a polymer. Use of a radioactive stent that is coated with radioactive isotopes for the manufacture of an implant for the prophylaxis of restenosis.