The Br(p,x)Se nuclear processes: a convenient route for the production of radioselenium tracers relevant to amino acid labelling

A possible route for the production of no-carrier-added (n.c.a.) ⁷³Se (T_1/2=7.1 h) and ⁷⁵Se (120 d) is introduced. -2-Amino-4-([⁷³Se]methyl-seleno) butanoic acid ( -[⁷³Se]selenomethionine) with an overall radiochemical yield of >40% could be prepared via a 3-step polymer-supported synthesis after successful separation of ⁷³Se from KBr targets. Excitation functions for the ^natBr(p,x) ^72,73,75Se processes were measured from threshold up to 100 MeV utilizing pellets of pressed KBr. Targets were irradiated at the NAC cyclotron with proton beams having primary energies of 40.4, 66.8 and 100.9 MeV. The calculated ⁷³Se yield (EOB) for 1 h irradiation in 1 μA of beam at the optimum proton energy range of 62→42 MeV is 81.4 MBq (2.2 mCi), and the calculated ⁷⁵Se yield (EOB) for the overall range 62 MeV→threshold for the same irradiation conditions is 0.97 MBq (0.026 mCi).     

Excitation functions of Se(d,xn)Br reactions: Comparative evaluation of possible routes for the production of Br at a small cyclotron

Excitation functions were measured for the first time for ⁷⁴Se(d,n)⁷⁵Br and ⁷⁴Se(d,2n)^74mBr reactions from threshold to 23 MeV. Use was made of the stacked-foil technique, and thin samples were prepared by electrolytic deposition of 31.4% enriched ⁷⁴Se on Al-backing. Differential and integral yields of ^74mBr and ⁷⁵Br were calculated from the measured excitation functions. The optimum energy range for the production of ⁷⁵Br via the ⁷⁴Se(d,n)-process was found to be E_d = 12 → 8 MeV, with ⁷⁵Br-yield amounting to 509 MBq (13.75 mCi)/μAh and the ^74mBr impurity to 78Kr(p,)⁷⁵Br and ⁷⁴Se(d,n)⁷⁵Br, suggested for the production of ⁷⁵Br at a small cyclotron is given. The (d,n) reaction gives higher yield than the (p,) process and is preferable at cyclotrons with E_d 10 MeV. In general, at a small cyclotron the achievable batch yields of ⁷⁵Br via both the processes are limited.     

The production of Xe via Xe(p,xn)Cs → Xe

Effective cross-sections for the production of ¹²⁷Cs in the bombardment of ^natXe with protons were measured from threshold up to 100 MeV. From the integral excitation function obtained, yield curves for ¹²⁷Xe, produced via the ^natXe(p,xn)¹²⁷Cs → ¹²⁷Xe route, were derived for a full range of gas target thicknesses. These curves can be used for the optimization of the production of ¹²⁷Xe within specific practical incident energy and target thickness constraints. The expected optimum yield for a representative production gas target (1.64 g/cm² thick) is 6.7 MBq/μAh (obtained at an incident energy of 39.3 MeV).     

Determination of specific radioactivity for (76)Br-labeled compounds measuring the ratio between (76)Br and (79)Br using packed capillary liquid chromatography mass spectrometry

Packed capillary liquid chromatography with electrospray mass spectrometry was used for direct determination of the specific radioactivity by calculation of isotope ratios between the ⁷⁶Br- and ⁷⁹Br-labeled analogues of N-((3-aminomethyl)benzyl)-4-bromobenzamide. Using 20 μL injections on packed capillary columns, sufficient mass sensitivity was attained for the determination on an injected amount of radioactivity corresponding to approximately 2 MBq (0.3 pmol of the ⁷⁶Br isotopic analogue).     

Excitation functions of proton induced reactions on cobalt: Production of no-carrier added nickel-57, a positron emitting label for doxorubicin

Excitation functions were measured, by the stacked-foil technique, for the ⁵⁹Co(p, 3n)⁵⁷Ni and ⁵⁹Co(p, 4n)⁵⁶Ni nuclear reactions from threshold up to 60 MeV. The excitation function for the ⁵⁹Co(p, 3n)⁵⁷Ni reaction shows a maximum cross section of 13.8±1.5 mb at 38 MeV. The optimum energy range for production of ⁵⁷Ni was found to be 41 → 26 MeV resulting in an experimental thick target yield of 19.3 MBq/μAh) (522 μCi/μAh). The level of the ⁵⁶Ni impurity is only 0.21% at EOB giving a ⁵⁷Ni product of 99.7% radionuclide purity at the time of use (24 h post EOB). Cross section data for the production of ⁵⁶Ni, ⁵⁶Co, ⁵⁷Co, ⁵⁸Co, ⁵²Mn, ⁵⁴Mn and ⁵¹Cr are also presented. A radiochemical procedure, based on cation-exchange chromatography, for the separation of radionickel from an activated cobalt target and other radiochemical and chemical impurities, has been developed. The ⁵⁷Ni activity was eluted, using 2 M HCl from a Dowex-50W × 8(H⁺) column, in a 95% radiochemical yield (15 mL). The ⁵⁷Ni has been used to label the anti-cancer drug, doxorubicin, thereby providing the means for pharmacokinetic and pharmacodynamic studies of this compound using positron emission tomography. The labelling has been optimized to give a radiochemical yield of >94%.     

Optimized indirect (76)Br-bromination of antibodies using N-succinimidyl para-[76Br]bromobenzoate for radioimmuno PET

Monoclonal antibody 38S1 was radiobrominated with the positron emitter ⁷⁶Br (T_1/2= 16.2 h). Indirect labeling was performed using N-succinimidyl para-(tri-methylstannyl)benzoate (SPMB) as the precursor molecule. SPMB was labeled using Chloramine-T yielding N-succinimidyl para-[⁷⁶Br]bromobenzoate, which was then conjugated to the antibody. Optimization of the labeling conditions and further conjugation gave a total yield ( mean±max error) of 49±2%. The immunoreactivity of the antibodies was retained after labeling. Thus, antibodies intended for positron emission tomography can be labeled with ⁷⁶Br, which gives high yields and preserved immunoreactivity when using the SPMB technique described.     

High yield direct Br-bromination of monoclonal antibodies using chloramine-T

Monoclonal antibody (MAb) A33 was labeled with the positron emitter ⁷⁶Br ( T_1/2=16.2 h). Direct labeling was done using the conventional chloramine-T method. After optimization of the labeling conditions, a maximum yield (mean ± max error) of 77 ± 2% was obtained at pH 6.8. In vitro binding of ⁷⁶Br-A33 to SW1222 colonic cancer cells showed that the immunoreactivity was retained. Also, the MAbs 38S1 and 3S193 and the peptide hEGF were ⁷⁶Br-labeled, resulting in labeling yields (mean ± max error) of 75 ± 3%, 63 ± 4%, and 73 ± 0.1%, respectively. We conclude that antibodies and peptides can be labeled conveniently with ⁷⁶Br for the purpose of whole-body tumour imaging by positron emission tomography.     

Formation of short-lived positron emitters in reactions of protons of energies up to 200 MeV with the target elements carbon, nitrogen and oxygen

Excitation functions were measured by the stacked-foil technique for proton induced reactions on carbon, nitrogen and oxygen leading to the formation of the short-lived positron emitters ¹¹C (T_1/2=20.38 min) and ¹³N (T_1/2=9.96 min). The energy region covered extended up to 200 MeV. The product activity was measured non-destructively via γ-ray spectrometry. A careful decay curve analysis of the positron annihilation radiation was invariably performed. The experimental results were compared with theoretical data obtained using the modified hybrid nuclear model code ALICE-IPPE for intermediate energies. The agreement was found to be generally satisfactory. The data are of importance in proton therapy.     

Cyclotron production of Ga(III) with a tandem Ge−Zn target

Production of ⁶⁷Ga(III) at the National Accelerator Centre is by proton bombardment of a ^natZn target, and uses 15−20 h of cyclotron beam time per production. A study was undertaken to use a tandem ^natGe−^natZn target to produce the same amount of ⁶⁷Ga, but using less beam time (7−8 h). ⁶⁷Ga(III) was separated from the tandem target material by a method based on acid dissolution of the target and chromatography on an organic polymer resin (Amberchrom™ CG−71cd) containing no ion exchange groups. The separated ⁶⁷Ga(III) has high radionuclidic purity and complies with the British and US Pharmacopoeia requirements for chemical purity.     

Experimental and theoretical excitation functions for Br(p,x) reactions

The excitation functions for protons incident on ^natBr were measured from threshold up to 100 MeV by means of the stacked-foil technique. Where applicable, the measured cross-section values are compared with previously published values. Theoretical cross-sections were also calculated by means of the computer code ALICE (IPPE) for comparison purposes.     

Measurements and nuclear model calculations on proton-induced reactions on Rh up to 40 MeV: evaluation of the excitation function of the Rh(p,n)Pd reaction relevant to the production of the therapeutic radionuclide Pd

Excitation functions were measured by the stacked-foil technique for the reactions ¹⁰³Rh(p,n)¹⁰³Pd, ¹⁰³Rh(p,3n)¹⁰¹Pd and ¹⁰³Rh(p,4n)¹⁰⁰Pd from their respective thresholds up to 39.6 MeV. The radioactivity of the activation products was determined by high-resolution X-ray and γ-ray spectrometry. Statistical model calculations taking into account the precompound effects were performed for all reactions, and good agreement was found with our data. A critical evaluation of the existing and present data for the ¹⁰³Rh(p,n)¹⁰³Pd reaction was carried out. Recommended cross sections and integral yields for this reaction of key importance in the production of the widely used therapeutic radionuclide ¹⁰³Pd are given.     

Development of an automated system for the quick production of N-labeled compounds with high specific activity using anhydrous [N]NH3

An automated system was developed to synthesize ¹³N-labeled compounds with high specific activity using anhydrous [¹³N]NH₃ as a synthetic precursor. This system enabled (1) production of an aqueous solution of [¹³N]NH₃, (2) concentration and desiccation of the [¹³N]NH₃ solution, (3) reaction of anhydrous [¹³N]NH₃ with substrate, (4) purification and formulation.

By the use of this system, [¹³N]p-nitrophenyl carbamate ([¹³N]NPC) ready for i.v. injection could be obtained in 5.1±0.1 min at the yield of 3.5±0.4 GBq, specific activity 460±55 GBq/μmol, and radiochemical purity >99% (n=3) by irradiating a 10 mM ethanol solution with 18 MeV protons at 17 μA for 25 min. With special precautions, [¹³N]NPC could be obtained at the extremely high specific activity of 1800±200 GBq/μmol.     

Preliminary results on the production of short-lived radioisotopes with a Plasma Focus device

An experimental campaign was conducted to assess the feasibility of short-lived radioisotope (SLR) production within the pulsed discharges of a Plasma Focus (PF) device. This so-called “endogenous production” technique rests on the exploitation of nuclear reactions for the creation of SLR directly within the plasma, rather than on irradiating an external target. Until now only one research group has published data relevant to PF endogenous production of SLR, and the data seem to confirm that the PF has the capability to breed SLR. The campaign demonstrated production of ¹⁵O, ¹⁷F and ¹³N from the ¹⁴N(d,n)¹⁵O, ¹²C(d,n)¹³N and ¹⁶O(d,n)¹⁷F reactions. A 7 kJ, 17 kV Mather-type PF was operated with natural nitrogen, oxygen, CO₂ and deuterium in the vacuum chamber. Results to date confirm that, with a PF of this type, up to 1 μCi of SLRs per discharge can be obtained.     

Production of Br by a low-energy cyclotron

We present a production method of a positron-emitting bromine isotope ⁷⁶Br (T_1/2=16.2 h) using a low-energy proton reaction ⁷⁶Se(p, n)⁷⁶Br. A pressed copper (I) selenide pellet containing enriched ⁷⁶Se is used as a target. Irradiation of a 180 mg/cm² target with 16→8 MeV protons gives a yield of 65–70 MBq/μAh EOB. In our target set-up with a simple water cooling, the target can withstand 14 μA. Bromine-76 is separated with an efficiency of 65–75%, within 60–75 min using dry distillation at 1090°C. The loss of target material is less than 1% per separation cycle and the target can be re-used several times. Thermal chromatography is applied to separate ⁷⁶Br from traces of volatilized selenium. The method allows a simple and economical production of ⁷⁶Br with the use of accelerators commonly available at PET-centers.     

Preparation of high specific activity (86)Y using a small biomedical cyclotron

⁸⁶Y is an attractive PET radionuclide due to its intermediate half-life. ⁸⁶Y was produced via the ⁸⁶Sr(p,n)⁸⁶Y nuclear reaction. Enriched SrCO₃ or SrO was irradiated with 2-6 μA of beam current for <4 h on a CS-15 cyclotron. It was shown that the SrO target could withstand at least 6 μA of beam current, a significant improvement over a maximum of 2 μA on the SrCO₃ target. Average yields of 4.5 mCi/μA·h were achieved with SrO, which represent 71% of the theoretical yield, compared to 2.3 mCi/μA·h with SrCO₃. The radioisotopic contaminants were ^86mY (220%), ⁸⁷Y (0.27%), ^87mY (0.43%) and ⁸⁸Y (0.024%). ⁸⁶Y was isolated in an electrochemical cell consisting of three Pt electrodes. The solution was electrolyzed at 2000 mA (40 min) using two Pt plate electrodes. A second electrolysis (230 mA for 20 min) was performed using one Pt plate and a Pt wire. On average, 97.1% of the ⁸⁶Y was recollected on the Pt wire after a second electrolysis. The ⁸⁶Y was collected from the Pt wire using 2.8 M HNO₃/EtOH (3:1). After evaporation, ⁸⁶Y was reconstituted in 100 μl of 0.1 M HCl. Target materials were recovered as SrCO₃ and then converted to SrO by thermal decomposition at 1150°C. Specific activity of ⁸⁶Y was determined to be 29±19 mCi/μg via titration of ⁸⁶Y(OAc)₃ with DOTA or DTPA. We have established techniques for the routine, economical production of high purity, high specific activity ⁸⁶Y on a small biomedical cyclotron that are translatable to other institutions.     

Experimental studies on the proton-induced activation reactions of molybdenum in the energy range 22–67 MeV

The production cross-sections of ^99,93mMo, ^96,95,95m,94Tc, ^96,95,92m,90Nb, ^89,88,86Zr and ^88,87,86Y radionuclides for proton-induced reactions on molybdenum were measured with molybdenum targets of natural isotopic composition using a stacked-foil activation technique in the energy range 22–67 MeV. The thick target integral yields were also deduced for each reaction using the measured cross-sections from the respective threshold up to 67 MeV. The results have given new data for all of the investigated radionuclides. The results of the present experiment showed excellent agreement with the earlier reported data in the lower energy region.     

Evaluation of peak-to-total ratio for germanium detectors

An equation for the peak-to-total ratio, P, of a germanium detector is proposed in the following form. P=_p/_t+a(V/A)+b(V/A)²/2 where _p/_t is the ratio of the photoelectric to the total detection efficiency for a germanium detector, V/A is the volume-to-surface ratio of the detector, and the parameters of a and b are experimentally given as a function of incident photon energy. The first term in the right side of the equation expresses the fractional single photoelectric-to-total interaction between photons and the detector. The second and third terms correspond to the multiple interactions. The peak-to-total ratios for the germanium detector with a sensitive volume up to 200 cm³ were calculated by the equation. They coincide with the experimental values to within an uncertainty of several percent in the energy region 0.3–3 MeV.     

Remote processing, delivery and injection of H2[O] produced from a N2/H2 gas target using a simple and compact apparatus

We report here a simple apparatus for remote trapping and processing of H₂[¹⁵O] produced from the N₂/H₂ target. The system performs a three step operation for H₂[¹⁵O] delivery at the PET imaging facility which includes the following: (i) collecting the radiotracer in sterile water; (ii) adjusting preparation pH through removal of radiolytically produced ammonia, while at the same time adjusting solution isotonicity; and (iii) delivery of the radiotracer preparation to the injection syringe in a sterile and pyrogen-free form suitable for human studies. The processing apparatus is simple, can be remotely operated and fits inside a Capintec Dose Monitoring Chamber for direct measurement of accumulated radioactivity. Using this system, 300 mCi of H₂[¹⁵O] (15 μA of 8 MeV D⁺ on target) is transferred from target through 120 m × 3.18 mm o.d. Impolene tubing to yield 100 mCi of H₂[¹⁵O] which is isotonic, neutral and suitable for human studies.

A remote hydraulically driven system for i.v. injection of the H₂[¹⁵O] is also described. The device allows for direct measurement of syringe dose while filling, and for easy, as well as safe transport of the injection syringe assembly to the patient's bedside via a shielded delivery cart. This cart houses a hydraulic piston that allows the physician to “manually” inject the radiotracer without directly handling the syringe.     

Automated synthesis and purification of [F]bromofluoromethane at high specific radioactivity

[¹⁸F]Bromofluoromethane was synthesised from dibromomethane by substitution of bromine with [¹⁸F]fluoride. The synthesis and separation of the [¹⁸F]bromofluoromethane were automated. [¹⁸F]Bromofluoromethane was used to convert a phenolic and a thiophenolic precursor into a labelled ether and thioether, respectively. The specific radioactivity of these labelled products was determined with both high-performance liquid chromatography (with UV-absorbance detection) and liquid chromatography (with mass spectrometric detection). The median for the specific radioactivity, corrected at the end of radionuclide production, was 934 GBq/μmol (range 40–9900 GBq/μmol; n=83).