Introduction Radioisotopes of bromine are of special interest for nuclear medical applications. The positron emitting isotopes 75Br (T½ = 1.6 h; β+ = 75.5 %) and 76Br (T½ = 16.2 h; β+ = 57 %) have suitable decay properties for molecular imaging with PET, while the Auger electron emitters 77Br (T½ = 57.0 h) and 80mBr (T½ = 4.4 h) as well as the β−-emitter 82Br (T½ = 35.3 h) are useful for internal radiotherapy. 77Br is additionally suited for SPECT. The isotopes 75Br, 76Br and 77Br are usually produced at a cyclotron either by 3He and α-particle induced reactions on natural arsenic or by proton and deuteron induced reactions on enriched selenium isotopes [1]. As target mate-rials for the latter two reactions, earlier ele-mental selenium [2] and selenides of Cu, Ag, Mn, Mo, Cr, Ti, Pb and Sn were investigated [cf. 3–7]. Besides several wet chemical separation techniques the dry distillation of bromine from the irradiated targets was investigated, too [cf. 2, 4, 5]. However, the method needs further development. Nickel selenide was investigated as a promising target to withstand high beam currents, and the dry distillation technique for the isolation of n.c.a. radiobromine from the target was optimized. Material and Methods Crystalline Nickel-(II) selenide (0.3–0.5 g) was melted into a 0.5 mm deep cavity of a 1 mm thick Ni plate covered with a Ni grid. NiSe has a melting point of 959 °C. For development of targeting and the chemical separation, natural target material was used. Irradiations of NiSe were usually performed with protons of 17 MeV using a slanting water cooled target holder at the cyclotron BC1710 [8]. For radiochemical studies a beam current of 3 µA and a beam time of about 1 h were appropriate. To separate the produced no-carrier-added (n.c.a.) radiobromine from the target material a dry distillation method was chosen. The apparatus was developed on the basis of a dry distillation method for iodine [cf. 9,10] and optimized to obtain the bromine as n.c.a. [*Br]bromide in a small volume of sodium hydroxide solution. Changing different components of the apparatus, the dead volume could be minimized and an almost constant argon flow as carrier medium was realized. Various capillaries of platinum, stainless steel and quartz glass with different diameters and lengths were tested to trap the radiobromine. Results and Conclusion Nickel selenide proved successful as target material for the production of radiobromine by proton irradiation with 17 MeV protons. The target was tested so far only at beam currents up to 10 µA, but further investigations are ongoing. The optimized dry distillation procedure allows trapping of 80–90 % of the produced radiobromine in a capillary. For this purpose quartz glass capillaries proved to be most suitable. After rinsing the capillary with 0.1 M NaOH solution the activity can be nearly completely obtained in less than 100 µL solution as [*Br]bromide immediately useable for radiosynthesis. So, the overall separation yield was estimated to 81 ± 5 %. The radionuclidic composition and activity of the separated radiobromide was measured by γ-ray spectrometry. Due to the use of natural selenium the determination of the isotopic purity was not meaningful, but it could be shown that the radiobromine was free from other radioisotopes co-produced in the target material and the backing. The radiochemical purity as well as the specific activity were determined by radio ionchromatography. Further experiments using NiSe produced from nickel and enriched selenium are to be per-formed. The isotopic purity of the produced respective radiobromide, the production yield at high beam currents and the reusability of the target material have to be studied.

Introduction 76Br is of interest for in vivo PET imaging applications. Its relatively long half-life (16.1 h) allows use not only on small molecules but also proteins which have slow excretion as carrier molecules. Irradiation using a low energy proton beam (~ 20 MeV) on an enriched Cu276Se target, followed by dry distillation with thermal chromatography, is one of the best methods to obtain sufficient amounts of 76Br for clinical applications1,2. However, the thermal chromatography is plagued by poor reproducibility and appears unsuitable for automation of its production, leading us to remove the thermal chroma-tography from the dry distillation. In this investigation we employed H2O solution to collect 76Br and optimized the distillation condition using a small amount of 77Br (57.0 h). We also produced large amount of 76Br under the optimized conditions to evaluate the dry distillation method. Material and Methods Target preparation and dry distillation were conducted based on the methods described in previous reports1,2. To produce 77Br, Cu2natSe target was irradiated with 20 MeV proton beams (5 µA) accelerated by AVF cyclotron in the Japan Atomic Energy Agency. The following two systems were used in the dry distillation optimization studies; (1) an initial system was composed of two furnaces, a main and an auxiliary furnace. Temperature of each furnace was set at 1050 °C (main) and 200 °C (auxiliary) respectively; (2) the second system was made of one large furnace composed of heating and cooling area. Temperature of the heating area was varied from 1050 to 1120 °C. In both systems PTFE tubing, leading to a H2O solution (15 mL), was inserted into the apparatus. The irradiated target was heated under streaming Ar gas (30 mL/min.). An enriched Cu276Se target (76Se enrichment: 99.67%) was used for 76Br production. Radioactivity was measured on a high-purity germanium (HPGe) detector coupled to a multichannel analyzer. TLC analyses were conducted on Al2O3 plates (Merck) using 7:1 acetone:H2O as the eluting solvent. Results and Conclusion Low efficiency (33 %) of 77Br recovery was ob-served in the initial system. Distribution of radioactivity inside the apparatus showed that 35 % was trapped in the PTFE tube and the quartz tube. The recovery yield was increased up to 54 % when the auxiliary furnace was turned off, indicating that the temperature gradient inside the quartz tube is suitable to carry 77Br effectively to the H2O trap. We initially used a quartz boat to place the irradiated target in the furnace, but found that using a reusable tungsten backing was better. However, we found that recovery yield was dramatically reduced to 18 %. The studies where the temperature was varied showed that releasing efficiency was increased up to 100 % at the temperature of 1120 °C. Good recovery yield (~ 77 %) was achieved after optimizing the temperature gradient (FIG. 1b). Using the optimized setup, 76Br production runs (n = 6) have been conducted, allowing us to recover up to 39.8 MBq/µAh (EOB) of 76Br. High specific activity (~4400 GBq/µmol) was obtained in the final solution. TLC analysis showed that chemical form obtained was bromide. We concluded that the dry distillation using H2O trap is capable of providing enough high purity 76Br for clinical applications.

Introduction 76Br is of interest for in vivo PET imaging applications. Its relatively long half-life (16.1 h) allows use not only on small molecules but also proteins which have slow excretion as carrier molecules. Irradiation using a low energy proton beam (~ 20 MeV) on an enriched Cu276Se target, followed by dry distillation with thermal chromatography, is one of the best methods to obtain sufficient amounts of 76Br for clinical applications1,2. However, the thermal chromatography is plagued by poor reproducibility and appears unsuitable for automation of its production, leading us to remove the thermal chroma-tography from the dry distillation. In this investigation we employed H2O solution to collect 76Br and optimized the distillation condition using a small amount of 77Br (57.0 h). We also produced large amount of 76Br under the optimized conditions to evaluate the dry distillation method. Material and Methods Target preparation and dry distillation were conducted based on the methods described in previous reports1,2. To produce 77Br, Cu2natSe target was irradiated with 20 MeV proton beams (5 µA) accelerated by AVF cyclotron in the Japan Atomic Energy Agency. The following two systems were used in the dry distillation optimization studies; (1) an initial system was composed of two furnaces, a main and an auxiliary furnace. Temperature of each furnace was set at 1050 °C (main) and 200 °C (auxiliary) respectively; (2) the second system was made of one large furnace composed of heating and cooling area. Temperature of the heating area was varied from 1050 to 1120 °C. In both systems PTFE tubing, leading to a H2O solution (15 mL), was inserted into the apparatus. The irradiated target was heated under streaming Ar gas (30 mL/min.). An enriched Cu276Se target (76Se enrichment: 99.67%) was used for 76Br production. Radioactivity was measured on a high-purity germanium (HPGe) detector coupled to a multichannel analyzer. TLC analyses were conducted on Al2O3 plates (Merck) using 7:1 acetone:H2O as the eluting solvent. Results and Conclusion Low efficiency (33 %) of 77Br recovery was ob-served in the initial system. Distribution of radioactivity inside the apparatus showed that 35 % was trapped in the PTFE tube and the quartz tube. The recovery yield was increased up to 54 % when the auxiliary furnace was turned off, indicating that the temperature gradient inside the quartz tube is suitable to carry 77Br effectively to the H2O trap. We initially used a quartz boat to place the irradiated target in the furnace, but found that using a reusable tungsten backing was better. However, we found that recovery yield was dramatically reduced to 18 %. The studies where the temperature was varied showed that releasing efficiency was increased up to 100 % at the temperature of 1120 °C. Good recovery yield (~ 77 %) was achieved after optimizing the temperature gradient (FIG. 1b). Using the optimized setup, 76Br production runs (n = 6) have been conducted, allowing us to recover up to 39.8 MBq/µAh (EOB) of 76Br. High specific activity (~4400 GBq/µmol) was obtained in the final solution. TLC analysis showed that chemical form obtained was bromide. We concluded that the dry distillation using H2O trap is capable of providing enough high purity 76Br for clinical applications.

Introduction Radioisotopes of bromine are of special interest for nuclear medical applications. The positron emitting isotopes 75Br (T½ = 1.6 h; β+ = 75.5 %) and 76Br (T½ = 16.2 h; β+ = 57 %) have suitable decay properties for molecular imaging with PET, while the Auger electron emitters 77Br (T½ = 57.0 h) and 80mBr (T½ = 4.4 h) as well as the β−-emitter 82Br (T½ = 35.3 h) are useful for internal radiotherapy. 77Br is additionally suited for SPECT. The isotopes 75Br, 76Br and 77Br are usually produced at a cyclotron either by 3He and α-particle induced reactions on natural arsenic or by proton and deuteron induced reactions on enriched selenium isotopes [1]. As target mate-rials for the latter two reactions, earlier ele-mental selenium [2] and selenides of Cu, Ag, Mn, Mo, Cr, Ti, Pb and Sn were investigated [cf. 3–7]. Besides several wet chemical separation techniques the dry distillation of bromine from the irradiated targets was investigated, too [cf. 2, 4, 5]. However, the method needs further development. Nickel selenide was investigated as a promising target to withstand high beam currents, and the dry distillation technique for the isolation of n.c.a. radiobromine from the target was optimized. Material and Methods Crystalline Nickel-(II) selenide (0.3–0.5 g) was melted into a 0.5 mm deep cavity of a 1 mm thick Ni plate covered with a Ni grid. NiSe has a melting point of 959 °C. For development of targeting and the chemical separation, natural target material was used. Irradiations of NiSe were usually performed with protons of 17 MeV using a slanting water cooled target holder at the cyclotron BC1710 [8]. For radiochemical studies a beam current of 3 µA and a beam time of about 1 h were appropriate. To separate the produced no-carrier-added (n.c.a.) radiobromine from the target material a dry distillation method was chosen. The apparatus was developed on the basis of a dry distillation method for iodine [cf. 9,10] and optimized to obtain the bromine as n.c.a. [*Br]bromide in a small volume of sodium hydroxide solution. Changing different components of the apparatus, the dead volume could be minimized and an almost constant argon flow as carrier medium was realized. Various capillaries of platinum, stainless steel and quartz glass with different diameters and lengths were tested to trap the radiobromine. Results and Conclusion Nickel selenide proved successful as target material for the production of radiobromine by proton irradiation with 17 MeV protons. The target was tested so far only at beam currents up to 10 µA, but further investigations are ongoing. The optimized dry distillation procedure allows trapping of 80–90 % of the produced radiobromine in a capillary. For this purpose quartz glass capillaries proved to be most suitable. After rinsing the capillary with 0.1 M NaOH solution the activity can be nearly completely obtained in less than 100 µL solution as [*Br]bromide immediately useable for radiosynthesis. So, the overall separation yield was estimated to 81 ± 5 %. The radionuclidic composition and activity of the separated radiobromide was measured by γ-ray spectrometry. Due to the use of natural selenium the determination of the isotopic purity was not meaningful, but it could be shown that the radiobromine was free from other radioisotopes co-produced in the target material and the backing. The radiochemical purity as well as the specific activity were determined by radio ionchromatography. Further experiments using NiSe produced from nickel and enriched selenium are to be per-formed. The isotopic purity of the produced respective radiobromide, the production yield at high beam currents and the reusability of the target material have to be studied.

<p>Different prosthetic groups containing a trialkylstannyl- and an electrophilic group have been synthesised and labelled with the accelerator produced ⁷⁶Br (T_1/2=16 h) through oxidative bromination. The labelled prosthetic groups were conjugated to amino-containing macromolecules such as proteins and 5´-modified oligonucleotides.</p><p><i>N</i>-Succinimidyl 4-[⁷⁶Br]bromobenzoate <b>14 </b>was synthesised in 65 % radio-chemical yield and was conjugated to 5´-hexylamino-modified phosphodiester and phosphorothioate oligonucleotides in 12-19 % isolated radiochemical yield. The stability of the ⁷⁶Br-oligonucleotide-conjugates <i>in vivo</i> in rats was investigated. No degradation from the 5´-end, resulting in labelled, low molecular weight compounds was detected. Compound <b>14</b> has also been used for labelling of different proteins in 23-61% radiochemical yield.</p><p><i>N</i>-Succinimidyl-5-[⁷⁶Br]bromo-3-pyridinecarboxylate <b>17</b> and methyl-4-[⁷⁶Br]bromo-benzimidate <b>15 </b>were synthesised from the corresponding trimethylstannyl-compound in 25% and 40 % yield respectively. Compounds <b>14 </b>and <b>17</b> were conjugated to ε-Boc-octreotide in 55 and 50% isolated radiochemical yield respectively after microwave heating. Compound <b>15</b> did not react with octreotide under the conditions investigated. The two ⁷⁶Br-labelled octreotide derivatives showed different lipophilicity and different binding-properties to tissue from meningiomas.</p><p>Hyaluronic acid, a polysaccharide, was modified with tyramine and labelled by oxidative bromination using ⁷⁶Br in 10% radiochemical yield.</p><p>The generator produced ⁶⁸Ga (T_1/2=68 min) was used to label octreotide and oligonucleotides modified with the metal chelating group 1,4,7,10-tetraazacyclo-dodecane-1,4,7,10-tetraacetic acid (DOTA). ⁶⁸Ga-DOTA-octreotide was isolated in 65% radiochemical yield and a phosphorothioated ⁶⁸Ga-DOTA-oligonucleotide was isolated in 35% radio-chemical yield after 30 min synthesis time.</p><p>Compound<b> 14 </b>was reacted with 3-aminomethylbenzylamine to give compound <b>18</b>. The specific radioactivity<b> </b>of<b> 18 </b>was determined to be 36 GBq/µmol by measuring the ratio between the mass-peaks for the ⁷⁶Br and ⁷⁹Br-compounds using packed-capillary LC-MS.</p>

Different prosthetic groups containing a trialkylstannyl- and an electrophilic group have been synthesised and labelled with the accelerator produced 76Br (T1/2=16 h) through oxidative bromination. The labelled prosthetic groups were conjugated to amino-containing macromolecules such as proteins and 5´-modified oligonucleotides. N-Succinimidyl 4-[76Br]bromobenzoate <b>14 </b>was synthesised in 65 % radio-chemical yield and was conjugated to 5´-hexylamino-modified phosphodiester and phosphorothioate oligonucleotides in 12-19 % isolated radiochemical yield. The stability of the 76Br-oligonucleotide-conjugates in vivo in rats was investigated. No degradation from the 5´-end, resulting in labelled, low molecular weight compounds was detected. Compound <b>14</b> has also been used for labelling of different proteins in 23-61% radiochemical yield. N-Succinimidyl-5-[76Br]bromo-3-pyridinecarboxylate <b>17</b> and methyl-4-[76Br]bromo-benzimidate <b>15 </b>were synthesised from the corresponding trimethylstannyl-compound in 25% and 40 % yield respectively. Compounds <b>14 </b>and <b>17</b> were conjugated to ε-Boc-octreotide in 55 and 50% isolated radiochemical yield respectively after microwave heating. Compound <b>15</b> did not react with octreotide under the conditions investigated. The two 76Br-labelled octreotide derivatives showed different lipophilicity and different binding-properties to tissue from meningiomas. Hyaluronic acid, a polysaccharide, was modified with tyramine and labelled by oxidative bromination using 76Br in 10% radiochemical yield. The generator produced 68Ga (T1/2=68 min) was used to label octreotide and oligonucleotides modified with the metal chelating group 1,4,7,10-tetraazacyclo-dodecane-1,4,7,10-tetraacetic acid (DOTA). 68Ga-DOTA-octreotide was isolated in 65% radiochemical yield and a phosphorothioated 68Ga-DOTA-oligonucleotide was isolated in 35% radio-chemical yield after 30 min synthesis time. Compound<b> 14 </b>was reacted with 3-aminomethylbenzylamine to give compound <b>18</b>. The specific radioactivity<b> </b>of<b> 18 </b>was determined to be 36 GBq/µmol by measuring the ratio between the mass-peaks for the 76Br and 79Br-compounds using packed-capillary LC-MS.