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).     

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.     

Standardization of a Re sodium perrhenate radiochemical solution using the TDCR method in liquid scintillation counting

Rhenium-186 has several current and potential applications in nuclear medicine. It decays by beta minus emissions mainly to the fundamental and the 137 keV excited levels of ¹⁸⁶Os and by electron capture to ¹⁸⁶W. This paper describes the standardization of this radionuclide using the Triple to Double Coincidence Ratio model (TDCR) method. This is done by the calculation of the energy transferred to the scintillator by considering the various decay/de-excitation paths following the disintegration of the nuclide. The uncertainty on the detection efficiency is evaluated by stochastic methods by considering statistical distribution of theoretical and experimental parameters used in the calculation model. The detection efficiency was found to be higher than 97%, allowing a relative standard uncertainty on the activity determination of about 0.3%.     

Recovery of F from [O] water by electrochemical method

An electrochemical method for producing ¹⁸F sources for the slow positron beam was applied to the recovery of ¹⁸F from H₂¹⁸O water. The ¹⁸F of activities 150–227 mCi (5.55–8.40 GBq) was electro-deposited on a graphite rod and then emitted into pure water. The best result of the efficiency for the electro-deposition for 5 min was 97% and that for the electro-emission for 5 min was 89%. The H₂¹⁸O water is expected to be reused much more easily by this method than by the ion exchange resin method. The metal impurities contained in the ¹⁸F solution were considerably reduced by using this method.     

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.     

Application of “wet” extrapolation method for activity standardisation of electron capture radionuclides

The activity of electron capture radionuclides is usually determined by 4π(proportional counter, PC)–γ coincidence counting. The corrections necessary for the final activity value calculation are obtained by an extrapolation method. Variation of the PC detection efficiency can be achieved through different methods, e.g. by changing the self-absorption of the source using absorbing foils or by adding carriers. Another possibility is a “wet” extrapolation method, which utilises an absorption change during the drying of a water droplet added onto the source surface. In this paper, slopes of extrapolation curves and resulting activity values obtained by different methods are compared for several radionuclides (⁵⁴Mn, ¹³⁹Ce, ⁸⁸Y, ⁵⁷Co). In some cases a digital coincidence system was used for the analysis of measured data. The “wet” extrapolation, due to its very simple procedure, seems to be convenient for routine measurement and its accuracy is similar to the other methods.     

Production of highly pure no-carrier added Zr for the labelling of antibodies with a positron emitter

⁸⁹Zr was produced in high amounts (130 mCi/h) via a (p,n) reaction on ⁸⁹Y. The ⁸⁹Zr-isotope was purified using a hydroxamate column. More than 95% of the Zr was eluted with 1 mL of 1 M oxalic acid. The radionuclidic purity was over 99.99%. The isolated ⁸⁹Zr quantitatively formed complexes with the chelating agent desferal at low concentrations (10–100 μM).     

α-Alkylation of amino acid derivatives: Synthesis and chiral resolution of [C]β-aminoisobutyric acid

A synthesis of ¹¹C-labeled β-aminoisobutyric acid ([¹¹C]β-AIB) and its enantiomeric resolution by high performance liquid chromatography (HPLC) are reported. β-Alanine ethyl ester 2 was converted to benzaldimine-β-alanine ethyl ester 3 in 87% yield. Treatment of the imine derivative 3 with lithium diisopropylamide (1.1 eq) in tetrahydrofuran at −78 °C, followed by addition of cold iodomethane (1.1 eq) produced the -methylated benzaldimine-β-alanine ethyl ester 4 in 73% chemical yield. Deprotection of the amino group by acidic hydrolysis followed by basic hydrolysis of the ester group produced the desired product 1 in 37% chemical yield. Labeling was accomplished using [¹¹C]methyl iodide. The radiola-beled product was purified by HPLC using a semipreparative reversed-phase C-18 column and 2 mM phosphate buffer (pH 5.9) as the mobile phase. The synthesis time was 35–40 min including HPLC purification, with 20–60% radiochemical yield (decay corrected). Radiochemical purity was >99%, with average specific activity being 450 mCi/μmol. Enantiomers of β-AIB were well separated by analytical HPLC using a chiral column and aqueous perchloric acid as the mobile phase. (S)-β-AIB was eluted at 17.4 min and the (R)-enantiomer was eluted at 20.0 min when the jacketed column was maintained at low temperature by circulation of ice-cold water, and the pH of the mobile phase was 1.05.     

Synthesis of the I- and I-labeled cholinergic nerve marker (-)-5-iodobenzovesamicol

The highly toxic curaremimetic and cholinergic neuron marker (−)-5-iodobenzovesamicol (IBVM) has been labeled with iodine-125 and iodine-123. [¹²⁵I]IBVM, suitable for animal distribution and ex vivo autoradiographic studies, was synthesized by solid-state exchange; isolated yields were 65–89% with specific activities in the range of 130–200 Ci/mmol. The synthesis of no-carrier-added (−)-5-[¹²⁵I]IBVM from the corresponding chiral (−)-5-(tri-n-butyltin) derivative using Na¹²⁵I was evaluated using the oxidants H₂O₂, peracetic acid and chloramine-T. Both peracetic acid and chloramine-T gave good yields (70–95%). However, when Na¹²³I was utilized, acceptable yields of [¹²³I]IBVM were obtained only with chloramine-T. Use of the latter oxidant did produce 5-chlorobenzovesamicol which was eliminated during HPLC purification. After optimization of the reaction parameters, [¹²³I]IBVM in batch sizes of 10–27 mCi, is routinely obtained with a specific activity of 30–70,000 Ci/mmol, radiochemical purity (>97%) and chiral purity (>98%). Isolated radiochemical yields have averaged 71% (N = 40). Distribution analyses of [¹²⁵I]IBVM and [¹²³I]IBVM in mice 4 h following intravenous administration show essentially equivalent concentrations of the two tracers in the four brain regions sampled. The exceptionally high specific activity of [¹²³I]IBVM has made possible the evaluation of this radiotracer in humans.     

High yield synthesis of high specific activity R-(−)-[C]epinephrine for routine PET studies in humans

R-(−)-[¹¹C]Epinephrine ([¹¹C]EPI) has been synthesized from R-(−)-norepinephrine by direct methylation with [¹¹C]methyl iodide or [¹¹C]methyl triflate. The total synthesis time including HPLC purification was 35–40 min. The radiochemical yields (EOB) were 5–10% for [¹¹C]methyl iodide and 15–25% for [¹¹C]methyl triflate. Radiochemical purity was >98%; optical purity determined by radio-chiral HPLC was >97%. The [¹¹C]methyl triflate technique produces R-(−)-[¹¹C]epinephrine in quantities (80–170 mCi) sufficient for multiple positron emission tomography studies in humans. The two synthetic methods are generally applicable to the production of other N-[¹¹C]methyl phenolamines and N-[¹¹C]methyl catecholamines.     

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.     

New renal function imaging agents. I. Synthesis and biological characterization of a [Tc]diaminomercapto(thio)ether (DAMTE)

The present study describes the synthesis of a [^99mTc]diaminomercapto(thio)ether (DAMTE-derivative) as a first compound of a new class of ^99mTc-complexes which is tubular excreted.

10-Benzoyl-8-keto-7-aza-2-amino-4,10-dithia-decanoic acid (CO₂-DAMTE 3) was synthesized by the reaction of succinimidyl-S-benzoyl-thioglycolate and (S)-2-aminoethyl- -cysteine. The respective technetium complex, ^99mTc---CO₂---DAMTE was obtained in radiochemical yields of about 70% using stannous chloride as reducing agent. Hydrolysis of the protecting group was performed either prior to the complexation of pertechnetate (“cold kit”) or during the labelling reaction (“hot kit”). Organ distribution was determined in Wistar rats. Within 24 h 40% of the activity were excreted into the feces and 43% into the urine, whereas 10% were retained in the kidneys. In contrast, a first human study showed a very fast renal elimination of ^99mTc---CO₂---DAMTE, a low liver uptake (< 10%) and no retention in the kidneys. The renal clearance of approx. 240 mL/min/1.73 m² in addition to the protein binding of > 95% suggests an effective tubular excretion of the compound.     

Preparation of carrier-free yttrium-90 for medical applications by solvent extraction chromatography

The separation of carrier-free ⁹⁰Y from fission product ⁹⁰Sr by solid supported solvent extraction chromatography was investigated using Teflon grain as solid support and a di-(2-ethylhexyl) phosphoric acid (D2EHPA) extraction agent as liquid phase. The optimum separation conditions are: (1) solid support using Dupont TF800 Teflon grains, (2) using 5% D2EHPA extraction agent as liquid phase, (3) setting the flow rate at 1 cm³/min, and (4) using a column diameter of 0.5 cm which was packed with 1 g treated Teflon. After loading ⁹⁰Sr/⁹⁰Y equilibrium solution, the loaded column was washed with 0.3 N hydrochloric acid to remove ⁹⁰Sr species; subsequently, 8 N hydrochloric acid was used as an eluent to obtain a ⁹⁰Y solution. Chemical yield was about 90%; radionuclide impurity of ⁹⁰Sr in the final product was <10⁻⁶%. Consequently, the preparation of 1 mCi of ⁹⁰Y was satisfactory for radiolabeling in medical applications. A radiotracer method using ⁸⁵Sr and ⁸⁸Y was also developed to investigate separation efficiency.     

Syntheses of carbon-11 labeled piperidine esters as potential in vivo substrates for acetylcholinesterase

A series of carbon-11 labeled N-methylpiperidinyl esters were prepared as potential in vivo substrates for acetylcholinesterase (AChE). Target compounds were designed based on the structure of N-[¹¹C]methylpiperidin-4-yl propionate, an ester currently used to measure AChE enzymatic activity in the human brain, to examine the structure–activity relationship for in vivo enzymatic hydrolysis. Changes in steric bulk and in the ester order (“reverse” esters) were made. Addition of methyl groups was made to both the acid side chain (synthesis of N-[¹¹C]methylmethylpiperidin-4-yl isobutyrate) and to the piperidine ring (syntheses of N-[¹¹C]methyl-4-methylpiperidin-4-yl propionate, N-[¹¹C]methyl-4-methylpiperidin-4-yl acetate, and N-[¹¹C]methyl-3-methylpiperidin-4-yl propionate). Alterations of the order of the ester heteroatoms was accomplished through syntheses of the N-[¹¹C]methyl-2,3- and 4-piperidinecarboxylic acid ethyl esters. Finally, an additional piperidine-based ester (N-[¹¹C]methylpiperidin-2-yl)methyl propionate was also prepared. All carbon-11-labeled esters were prepared by N-[¹¹C]methylation reactions, using the desmethyl precursors and no-carrier-added [¹¹C]methyltriflate, and were obtained in decay-corrected yields (not optimized) of 10–40% and high specific activities.     

Radium-228 determination of natural waters via concentration on manganese dioxide and separation using Diphonix ion exchange resin

The objective of this work was to establish a new procedure for ²²⁸Ra determination of natural waters via preconcentration of radium on MnO₂ and separation of its daughter, ²²⁸Ac, using Diphonix ion exchange resin. Following removal of potential interferences via passage through an initial Diphonix Resin column, the first daughter of ²²⁸Ra, ²²⁸Ac, is isolated by chromatographic separation via a second Diphonix column. A holding time of >30 h for ²²⁸Ac ingrowth in between the two column separations ensures secular equilibrium. Barium-133 is used as a yield tracer. Actinium-228 is eluted from the second Diphonix Resin with 5 ml 1 M 1-Hydroxyethane-1,1-diphosphonic acid (HEDPA) and quantified by addition of scintillation cocktail and LSC counting. Radium (and ¹³³Ba) from the load and rinse solutions from the 2nd Diphonix column may be prepared for alpha spectrometry (for determination of ²²³Ra, ²²⁴Ra, and ²²⁶Ra) by BaSO₄ microprecipitation and filtration. Decontamination tests indicate that U, Th, and Ra series nuclides do not interfere with these measurements, although high contents of ⁹⁰Sr (⁹⁰Y) require additional treatment for accurate measurement of ²²⁸Ra. Addition of stable Sr as a “hold back” carrier during the initial MnO₂ preconcentration step was shown to remove most ⁹⁰Sr interference.     

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%.     

Whole-body radiation dosimetry of 2-[18F]Fluoro-A-85380 in human PET imaging studies

2-[¹⁸F]Fluoro-A-85380 (2-[¹⁸F]fluoro-3-(2(S)-azetidinylmethoxy)pyridine, 2-[¹⁸F]FA) is a recently developed PET radioligand for noninvasive imaging of nicotinic acetylcholine receptors. Previous radiation absorbed dose estimates for 2-[¹⁸F]FA were limited to evaluation of activity in only several critical organs. Here, we performed 2-[¹⁸F]FA radiation dosimetry studies on two healthy human volunteers to obtain data for all important body organs. Intravenous injection of 2.9 MBq/kg of 2-[¹⁸F]FA was followed by dynamic PET imaging. Regions of interest were placed over images of each organ to generate time–activity curves, from which we computed residence times. Radiation absorbed doses were calculated from the residence times using the MIRDOSE 3.0 program (version 3.0, ORISE, Oak Ridge, TN). The urinary bladder wall receives the highest radiation absorbed dose (0.153 mGy/MBq, 0.566 rad/mCi, for a 2.4-h voiding interval), followed by the liver (0.0496 mGy/MBq, 0.184 rad/mCi) and the kidneys (0.0470 mGy/MBq, 0.174 rad/mCi). The mean effective dose equivalent is estimated to be 0.0278 mSv/MBq (0.103 rem/mCi), indicating that radiation dosimetry associated with 2-[¹⁸F]FA is within acceptable limits.     

A kit for labeling of [Re] human serum albumin microspheres for therapeutic use in nuclear medicine

Intra-arterial infusion of labeled particles is an effective method for local endoradiotherapy of tumors. In this study, we present an efficient method of radiolabeling biodegradable human serum albumin (HSA) microspheres with the short-lived beta-emitter ¹⁸⁸Re using a simple and reliable kit. Up to now, it was not possible to label particles with more than 85–90% efficiency. Under optimized reaction conditions, we achieved nearly 100% uptake of ¹⁸⁸Re. Using the proposed kit, we added tartrate solution and increased the pH from 2 to 4–5 after 1 h reaction time at 95 °C. The ¹⁸⁸Re binding to the particles was found to be stable in vitro.     

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.     

F-18 Polyethyleneglycol stilbenes as PET imaging agents targeting Abeta aggregates in the brain

This paper describes a novel series of ¹⁸F-labeled polyethyleneglycol (PEG)-stilbene derivatives as potential β-amyloid (Aβ) plaque-specific imaging agents for positron emission tomography (PET). In these series of compounds, ¹⁸F is linked to the stilbene through a PEG chain, of which the number of ethoxy groups ranges from 2 to 5. The purpose of adding PEG groups is to lower the lipophilicity and improve bioavailability. The syntheses of the “cold” compounds and the ¹⁸F-labeled PEG stilbene derivatives are successfully achieved. All of the fluorinated stilbenes displayed high binding affinities in an assay using postmortem AD brain homogenates (K_i=2.9–6.7 nM). Labeling was successfully performed by a substitution of the mesylate group of 10a–d by [¹⁸F]fluoride giving the target compounds [¹⁸F]12a–d (EOS, specific activity, 900–1500 Ci/mmol; radiochemical purity >99%). In vivo biodistribution of these novel ¹⁸F ligands in normal mice exhibited excellent brain penetrations and rapid washouts after an intravenous injection (6.6–8.1 and 1.2–2.6 %dose/g at 2 and 60 min, respectively). Autoradiography of postmortem AD brain sections of [¹⁸F]12a–d confirmed the specific binding related to the presence of Aβ plaques. In addition, in vivo plaque labeling can be clearly demonstrated with these ¹⁸F-labeled agents in transgenic mice (Tg2576), a useful animal model for Alzheimer's disease. In conclusion, the preliminary results strongly suggest these fluorinated PEG stilbene derivatives are suitable candidates as Aβ plaque imaging agents for studying patients with Alzheimer's disease.