Evaluation of several multiple diglycolamide-functionalized calix[4]arene ligands for the isolation of carrier free 90Y from 90Sr

Several diglycolamide-functionalized calix[4]arenes containing four and eight diglycolamide (DGA) moieties were evaluated for their relative extraction efficiencies towards Y(III) and Sr(II). Ligands containing four DGA units with n-propyl, iso-pentyl, and n-octyl groups at the amidic N atom adjacent to the calix[4]arene skeleton showed efficient extraction of Y(III) from 3 M HNO₃. The extraction of Sr(II) was poor in all cases in the entire acidity range (0.1–6 M HNO₃) studied. The ligands with a hydrogen atom and an n-propyl group at the concerning amidic N atom showed a very high separation efficiency as reflected in separation factor (S.F.=D_Y/D_Sr) values in the range of 10⁵–10⁶. A method was developed for the separation of carrier-free ⁹⁰Y from a ⁹⁰Y-⁹⁰Sr mixture involving consecutive extraction–stripping cycles. The product purity was checked using half-life measurements. Two consecutive cycles of extraction and stripping were found to be sufficient for obtaining pure ⁹⁰Y. The results obtained in the present studies were compared with those obtained previously using analogous ligands such as TODGA (N,N,N',N'-tetraoctyl diglycolamide), T2EHDGA (N,N,N',N'-tetra-2-ethylhexyl diglycolamide), and PC-88A (bis(2-ethylhexyl) phosphonic acid).     

Role of diluent on the separation of Y from Sr by solvent extraction and supported liquid membrane using T2EHDGA as the extractant

The separation behaviour of ⁹⁰Y from ⁹⁰Sr was investigated by diluent variation using solvent extraction and supported liquid membrane techniques employing N,N,N′,N′-tetra-2-ethylhexyldiglycolamide (T2EHDGA) as the extractant. Both D_Y (distribution ratio of Y(III)) and S.F. (separation factor) were found to be high in the solvent extraction studies when chloroform was used as the diluent. Subsequent supported liquid membrane (SLM) studies using PTFE flat sheet membranes containing 0.2 M T2EHDGA in various diluents indicated the trend of Y transport as xylene>hexone>chloroform>carbon tetrachloride>n-dodecane+30% iso-decanol mixture. However, the Sr(II) transport rates were also high with xylene, hexone, and carbon tetrachloride as the diluents which led us to carry out subsequent studies using chloroform and n-dodecane+30% iso-decanol mixture. Acid variation studies in chloroform system indicated an interesting phenomena of increasing Y(III) transport and decreasing Sr(II) transport with increasing acid concentration. Separation of ⁹⁰Y from a mixture of ⁹⁰Sr and ⁹⁰Y was also attempted.     

The Relative Distributions of Radioactive Yttrium and Strontium and the Secondary Deposition of 90Y Built up from 90Sr

Weanling rabbits were injected intravenously with one of three solutions: (1) ⁹⁰Sr (free from ⁹⁰Y), (2) ⁹⁰Sr + ⁹⁰Y in equilibrium, and (3) ⁹¹Y, to compare the relative distributions of strontium and yttrium and to establish whether ⁹⁰Y formed by ⁹⁰Sr decay escaped from sites of its original deposition. The animals were sacrificed at different times up to 30 days after injection, and samples of bone and soft tissues were assayed by means of a beta scintillation counter. The measurements on bone showed the concentrations (in µc/g of bone) of strontium and yttrium to be approximately equal. Soft tissues showed a much higher concentration of yttrium than of strontium, but those having highest concentrations of yttrium also had relatively high concentrations of strontium, namely cartilage, pituitary and kidney.

Measurements of the ⁹⁰Y built up when ⁹⁰Sr (free from ⁹⁰Y) was injected showed that ⁹⁰Y was built up in the liver in excess of the amount predicted from the deposition of ⁹⁰Sr.     

Strontium-90 Induced Bone Tumours in Beagle Dogs: Effects of Route of Exposure and Dose Rate

Bone tumours from beagles exposed by inhalation to ⁹⁰SrCl₂ at the Inhalation Toxicology Research Institute (ITRI), by chronic ingestion of ⁹⁰Sr at the Laboratory of Energy-Related Health Research (LEHR), and by injection of ⁹⁰Sr citrate at the University of Utah were analysed to determine if the bone tumour characteristics differed among the three studies. The range of average skeletal doses at which the bone tumours occurred was similar in all three studies, but differences in the skeletal distribution, histological phenotype, and time to death were observed. The differences observed were attributed to the difference in dose-rate pattern obtained in the chronic ingestion study, in contrast to the inhalation and injection studies. In general, however, the differences noted in bone tumour characteristics were subtle, and would be unlikely to make an impact on models developed to assess the risk of human exposure to ⁹⁰Sr.     

Results of an EC laboratory comparison on 40K, 90Sr and 137Cs in dried bilberry powder

The evaluation is presented of a laboratory comparison (LC) on ⁹⁰Sr, ⁴⁰K and ¹³⁷Cs in dried bilberries organised in 2011 by the IRMM. The activity concentrations reported by 88 participant laboratories are compared to the reference values of the new reference material IRMM-426 Wild Berries. Nine per cent and 17% of activity concentration results for ¹³⁷Cs and ⁴⁰K, respectively, deviate more than 20% from the reference values, a result worse than that obtained in previous LCs. For ⁹⁰Sr, about 88% of results lie within 30% of the reference value, better than observed in previous LCs. But only 58% of ⁹⁰Sr results are satisfactory in terms of the E_n criterion, indicating difficulties with a complete uncertainty estimation.     

Comparative study on DOTA-derivatized bombesin analog labeled with Y and Lu: in vitro and in vivo evaluation

IntroductionThe aim of the study was to compare in vitro and in vivo a novel DOTA-chelated bombesin (BN) analog of the amino acid sequence, QRLGNQWAVGHLM-CONH₂ (BN[2–14]NH₂), labeled with ⁹⁰Y and ¹⁷⁷Lu, for its potential use in targeted radiotherapy of tumors expressing gastrin releasing peptide (GRP) receptors. The same amino acid sequence, but with different chelator, referred as BN1.1 (Gly-Gly-Cys-Aca-QRLGNQWAVGHLM-CONH₂), has already been studied and reported; however, the DOTA-chelated one, suitable for labeling with M⁺³ type radiometals, was not yet described.MethodsThe conditions for labeling of DOTA-BN[2–14]NH₂ with noncarrier added ⁹⁰Y and with ¹⁷⁷Lu [specific activity (SA), 15 Ci/mg Lu] were investigated and optimized to provide ⁹⁰Y-DOTA-BN[2–14]NH₂ and ¹⁷⁷Lu-DOTA-BN[2–14]NH₂ of high SA. The stability of the radiolabeled compounds in human serum was evaluated over a period of 24 h. The human prostate cancer cell line PC-3, known to express GRP receptors, was used for in vitro evaluation of radiolabeled peptide affinity to GRP receptors and for assessment of cytotoxicity of both nonlabeled and radiolabeled peptide. Biodistribution accompanied by receptor blocking was studied in normal Swiss mice.Results⁹⁰Y-DOTA-BN[2–14]NH₂ and ¹⁷⁷Lu-DOTA-BN[2–14]NH₂ were obtained with radiochemical yield >98% and high SA (67.3 GBq ⁹⁰Y/μmol and 33.6 GBq ¹⁷⁷Lu/μmol, respectively). They were stable when incubated in human serum for up to 24 h. The binding affinities of DOTA-BN[2–14]NH₂ and both ^natY- and ^natLu-labeled analogs to GRP receptors were high (IC₅₀=1.78, 1.99, and 1.34 nM, respectively), especially for the ^natLu-DOTA-BN[2–14]NH₂ complex. The cytotoxicity study of DOTA-BN[2–14]NH₂ to PC-3 cells revealed an IC₅₀=6300 nM after 72 h of exposition, while the labeled derivatives showed no significant cytotoxic effect. The internalization rate to PC-3 cells was more rapid for ¹⁷⁷Lu-labeled peptide (84.87%) than for the ⁹⁰Y-labeled one (80.79%), while the efflux rate was slower for ¹⁷⁷Lu-DOTA-BN[2–14]NH₂ (46.8% vs. 61.74%). The biodistribution study of both derivatives in normal mice revealed a specific binding to GRP receptor-positive tissues, which could be blocked by coinjection of cold peptide. The effect of receptor blockage in vivo was also more pronounced for the ¹⁷⁷Lu-labeled peptide than that for the ⁹⁰Y-labeled (81% vs. 42%, respectively).ConclusionsOur studies demonstrated that DOTA-BN[2–14]NH₂ can be labeled with ⁹⁰Y (NCA) and ¹⁷⁷Lu (CA) with high radiochemical yields. The in vitro and in vivo comparison between ⁹⁰Y-DOTA-BN[2–14]NH₂ and ¹⁷⁷Lu-DOTA-BN[2–14]NH₂ indicated that the change of radiometal in the complex from Y to Lu influence the binding affinity to the GRP receptors with preference to the ¹⁷⁷Lu-labeled derivative.     

Excitation functions of high-energy 3He- and alpha-particle induced nuclear reactions on natural krypton with special reference to the production of 82Sr

Excitation functions were measured for ^natKr(³He, xn)^82,83,85Sr and ^natKr(³He, pxn)^83,84,86Rb reactions over the energy range 20–92 MeV, and for ^natKr(α, xn)^82,83,85Sr and ^natKr(α, pxn)^83,84,86Rb processes from 20 to 120 MeV. Thick target yields of ^82,83,85Sr were calculated. At a given incident energy, the ³He-particle induced process gives a higher ⁸²Sr-yield than the α-particle process. For E_3He = 90→20 MeV the expected ⁸²Sr-yield is 35 μCi (1290 kBq)/μAh and the ⁸⁵Sr/⁸²Sr ratio is 0.35. For E_α = 120→20 MeV the calculated yield of ⁸²Sr amounts to 52 μCi (1920 kBq)/μAh and the ⁸⁵Sr/⁸²Sr ratio is 1.24.     

Radiotracers for cardiac sympathetic innervation: Transport kinetics and binding affinities for the human norepinephrine transporter

IntroductionMost radiotracers for imaging of cardiac sympathetic innervation are substrates of the norepinephrine transporter (NET). The goal of this study was to characterize the NET transport kinetics and binding affinities of several sympathetic nerve radiotracers, including [¹¹C]-(?)-meta-hydroxyephedrine, [¹¹C]-(?)-epinephrine, and a series of [¹¹C]-labeled phenethylguanidines under development in our laboratory. For comparison, the NET transport kinetics and binding affinities of some [³H]-labeled biogenic amines were also determined.MethodsTransport kinetics studies were performed using rat C6 glioma cells stably transfected with the human norepinephrine transporter (C6-hNET cells). For each radiolabeled NET substrate, saturation transport assays with C6-hNET cells measured the Michaelis–Menten transport constants K_m and V_max for NET transport. Competitive inhibition binding assays with homogenized C6-hNET cells and [³H]mazindol provided estimates of binding affinities (K_I) for NET.ResultsK_m, V_max and K_I values were determined for each NET substrate with a high degree of reproducibility. Interestingly, C6-hNET transport rates for ‘tracer concentrations’ of substrate, given by the ratio V_max/K_m, were found to be highly correlated with neuronal transport rates measured previously in isolated rat hearts (r² = 0.96). This suggests that the transport constants K_m and V_max measured using the C6-hNET cells accurately reflect in vivo transport kinetics.ConclusionThe results of these studies show how structural changes in NET substrates influence NET binding and transport constants, providing valuable insights that can be used in the design of new tracers with more optimal kinetics for quantifying regional sympathetic nerve density.     

Development of [90Y]DOTA-conjugated bisphosphonate for treatment of painful bone metastases

IntroductionBased on the concept of bifunctional radiopharmaceuticals, we have previously developed ¹⁸⁶Re-complex-conjugated bisphosphonate analogs for palliation of painful bone metastases and have demonstrated the utility of these compounds. By applying a similar concept, we hypothesized that a bone-specific directed ⁹⁰Y-labeled radiopharmaceutical could be developed.MethodsIn this study, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) was chosen as the chelating site, and DOTA was conjugated with 4-amino-1-hydroxybutylidene-1,1-bisphosphonate. [⁹⁰Y]DOTA-complex-conjugated bisphosphonate ([⁹⁰Y]DOTA-HBP) was prepared by coordination with ⁹⁰Y, and its biodistribution was studied in comparison to [⁹⁰Y]citrate.ResultsIn biodistribution experiments, [⁹⁰Y]DOTA-HBP and [⁹⁰Y]citrate rapidly accumulated and resided in the bone. Although [⁹⁰Y]citrate showed a higher level of accumulation in the bone than [⁹⁰Y]DOTA-HBP, the clearances of [⁹⁰Y]DOTA-HBP from the blood and from almost all soft tissues were much faster than those of [⁹⁰Y]citrate. As a result, the estimated absorbed dose ratios of soft tissues to osteogenic cells (target organ) of [⁹⁰Y]DOTA-HBP were lower than those of [⁹⁰Y]citrate.Conclusions[⁹⁰Y]DOTA-HBP showed superior biodistribution characteristics as a bone-seeking agent and led to a decrease in the level of unnecessary radiation compared to [⁹⁰Y]citrate. Since the DOTA ligand forms a stable complex not only with ⁹⁰Y but also with lutetium (¹⁷⁷Lu), indium (¹¹¹In), gallium (^67/68Ga), gadolinium (Gd) and so on, complexes of DOTA-conjugated bisphosphonate with various metals could be useful as agents for palliation of metastatic bone pain, bone scintigraphy and magnetic resonance imaging.     

Systemic catechol-O-methyl transferase inhibition enables the D1 agonist radiotracer R-[11C]SKF 82957

IntroductionR-[¹¹C]-SKF 82957 is a high-affinity and potent dopamine D₁ receptor agonist radioligand, which gives rise to a brain-penetrant lipophilic metabolite. In this study, we demonstrate that systemic administration of catechol-O-methyl transferase (COMT) inhibitors blocks this metabolic pathway, facilitating the use of R-[¹¹C]-SKF 82957 to image the high-affinity state of the dopamine D₁ receptor with PET.MethodsR-[¹¹C]SKF 82957 was administered to untreated and COMT inhibitor-treated conscious rats, and the radioactive metabolites present in the brain and plasma were quantified by HPLC. Under optimal conditions, cerebral uptake and dopamine D₁ binding of R-[¹¹C]SKF 82957 were measured ex vivo. In addition, pharmacological challenges with the receptor antagonist SCH 23390, amphetamine, the dopamine reuptake inhibitor RTI-32 and the dopamine hydroxylase inhibitor α-methyl-p-tyrosine were performed to study the specificity and sensitivity of R-[¹¹C]-SKF 82957 dopamine D₁ binding in COMT-inhibited animals.ResultsTreatment with the COMT inhibitor tolcapone was associated with a dose-dependent (EC₉₀ 5.3±4.3 mg/kg) reduction in the lipophilic metabolite. Tolcapone treatment (20 mg/kg) also resulted in a significant increase in the striatum/cerebellum ratio of R-[¹¹C]SKF 82957, from 15 (controls) to 24. Treatment with the dopamine D₁ antagonist SCH 23390 reduced the striatal binding to the levels of the cerebellum, demonstrating a high specificity and selectivity of R-[¹¹C]SKF 82957 binding.ConclusionsPre-treatment with the COMT inhibitor tolcapone inhibits formation of an interfering metabolite of R-[¹¹C]SKF 82957. Under such conditions, R-[¹¹C]SKF 82957 demonstrates high potential as the first agonist radiotracer for imaging the dopamine D₁ receptor by PET.     

Test-retest reproducibility of dopamine D2/3 receptor binding in human brain measured by PET with [11C]MNPA and [11C]raclopride

Purpose

Dopamine D_2/3 receptors (D_2/3Rs) have two affinity states for endogenous dopamine, referred to as high-affinity state (D_2/3 ^HIGH), which has a high affinity for endogenous dopamine, and low-affinity state (D_2/3 ^LOW). The density of D_2/3 ^HIGH can be measured with (R)-2-¹¹CH₃O-N-n-propylnorapomorphine ([¹¹C]MNPA), while total density of D_2/3 ^HIGH and D_2/3 ^LOW (D_2/3Rs) can be measured with [¹¹C]raclopride using positron emission tomography (PET). Thus, the ratio of the binding potential (BP) of [¹¹C]MNPA to that of [¹¹C]raclopride ([¹¹C]MNPA/[¹¹C]raclopride) may reflect the proportion of the density of D_2/3 ^HIGH to that of D_2/3Rs. In the caudate and putamen, [¹¹C]MNPA/[¹¹C]raclopride reflects the proportion of the density of D₂ ^HIGH to that of D₂Rs. To evaluate the reliability of the PET paradigm with [¹¹C]MNPA and [¹¹C]raclopride, we investigated the test-retest reproducibility of non-displaceable BP (BP _ND) measured with [¹¹C]MNPA and of [¹¹C]MNPA/[¹¹C]raclopride in healthy humans.

Methods

Eleven healthy male volunteers underwent two sets of PET studies on separate days that each included [¹¹C]MNPA and [¹¹C]raclopride scans. BP _ND values in the caudate and putamen were calculated. Test-retest reproducibility of BP _ND of [¹¹C]MNPA and [¹¹C]MNPA/[¹¹C]raclopride was assessed by intra-subject variability (absolute variability) and test-retest reliability (intraclass correlation coefficient: ICC).

Results

The absolute variability of [¹¹C]MNPA BP _ND was 5.30?±?3.96 % and 12.3?±?7.95 % and the ICC values of [¹¹C]MNPA BP _ND were 0.72 and 0.82 in the caudate and putamen, respectively. The absolute variability of [¹¹C]MNPA/[¹¹C]raclopride was 6.11?±?3.68 % and 11.60?±?5.70 % and the ICC values of [¹¹C]MNPA/[¹¹C]raclopride were 0.79 and 0.80 in the caudate and putamen, respectively.

Conclusion

In the present preliminary study, the test-retest reproducibility of BP _ND of [¹¹C]MNPA and of [¹¹C]MNPA/[¹¹C]raclopride was reliable in the caudate and putamen.     

Rapid solid-phase extraction method to quantify [C]-verapamil, and its [C]-metabolites, in human and macaque plasma

IntroductionP-glycoprotein (P-gp), an efflux transporter, is a significant barrier to drug entry into the brain and the fetus. The positron emission tomography (PET) ligand, [¹¹C]-verapamil, has been used to measure in vivo P-gp activity at various tissue–blood barriers of humans and animals. Since verapamil is extensively metabolized in vivo, it is important to quantify the extent of verapamil metabolism in order to interpret such P-gp activity. Therefore, we developed a rapid solid-phase extraction (SPE) method to separate, and then quantify, verapamil and its radiolabeled metabolites in plasma.MethodsUsing high-performance liquid chromatography (HPLC), we established that the major identifiable circulating radioactive metabolite of [¹¹C]-verapamil in plasma of humans and the nonhuman primate, Macaca nemestrina, was [¹¹C]-D-617/717. Using sequential and differential pH elution on C₈ SPE cartridges, we developed a rapid method to separate [¹¹C]-verapamil and [¹¹C]-D-617/717. Recovery was measured by spiking the samples with the corresponding nonradioactive compounds and assaying these compounds by HPLC.ResultsVerapamil and D-617/717 recovery with the SPE method was >85%. When the method was applied to PET studies in humans and nonhuman primates, significant plasma concentration of D-617/717 and unknown polar metabolite(s) were observed. The SPE and the HPLC methods were not significantly different in the quantification of verapamil and D-617/717.ConclusionsThe SPE method simultaneously processes multiple samples in less than 5 min. Given the short half-life of [¹¹C], this method provides a valuable tool to rapidly determine the concentration of [¹¹C]-verapamil and its [¹¹C]-metabolites in human and nonhuman primate plasma.     

Development of an automated system for the quick production of 13N-labeled compounds with high specific activity using anhydrous [13N]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.     

Pretreatment quantitative 18F-FDG PET/CT parameters as a predictor of survival in adenoid cystic carcinoma of the salivary glands

PurposeThe aim of this study was to determine the unique prognostic value of quantitative ¹⁸F-FDG PET/CT parameters to assess progression-free survival (PFS), distant metastasis-free survival (DMFS), and overall survival (OS) in patients with salivary gland adenoid cystic carcinoma (ACC).MethodsWe performed a retrospective study including 23 patients (15 men, 8 women; median age, 58 years; range, 21–91 years) with salivary gland ACC between January 2009 and October 2017 who underwent ¹⁸F-FDG PET/CT scan prior to treatment. Maximum, mean, peak, tumor-to-mediastinal blood pool and tumor-to-liver standardized uptake values (SUV_max, SUV_mean, SUV_peak, SUV_ratio[med] and SUV_ratio[liver]), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were obtained from ¹⁸F-FDG PET/CT. The prognostic value of quantitative ¹⁸F-FDG PET/CT parameters and other clinicopathological variables were evaluated utilizing the Cox proportional regression analysis.ResultsThe 3-year and 5-year OS for all the patients were 90.9%, and 62.3%, respectively. Log rank test determined that the SUV_ratio[med], SUV_ratio[liver], MTV and TLG were predictive factors of DMFS, PFS, and OS (p < 0.05), furthermore, SUV_max, minor salivary gland tumors and DM at initial diagnosis (M1 stage) were predictor for PFS; M1 stage and overall stage 3–4 predicted DMFS (all p < 0.05). Cox regression analyses confirmed that the higher SUV_ratio[med], SUV_ratio[liver], MTV, and TLG values predicted DMFS, PFS and OS independently, whereas SUV_max was an independent predictor of only PFS (p < 0.05).ConclusionsThe pretreatment metabolic ¹⁸F-FDG PET/CT parameters may reflect tumor aggressiveness in patients with salivary gland ACC and may potentially be utilized as a prognostic biomarker.     

170Tm-EDTMP: a potential cost-effective alternative to 89SrCl2 for bone pain palliation

IntroductionMetastron (⁸⁹SrCl₂) is a radiopharmaceutical currently used for bone pain palliation in several countries since the long half-life of ⁸⁹Sr (50.5 days) favors wider distribution than other radioisotopes approved for this application, which have shorter half-lives. Strontium-89 is not ideal for bone pain palliation due to its high energy β^? particle emission [E_β(max)=1.49 MeV] and is also difficult to produce in large quantities. A ¹⁷⁰Tm [T_1/2=128.4 days, E_β(max)=968 keV, E_γ=84 keV (3.26%)]-based radiopharmaceutical for bone pain palliation could offer significant advantages over that of ⁸⁹Sr. The present study constitutes the first report of the preparation of a ¹⁷⁰Tm-based agent, ¹⁷⁰Tm-ethylenediaminetetramethylene phosphonic acid (EDTMP), and its preliminary biological evaluation in animal models.Methods¹⁷⁰Tm was produced by thermal neutron bombardment on natural Tm₂O₃ target for a period of 60 days at a flux of 6×10¹³ neutrons/cm².s. ¹⁷⁰Tm-EDTMP complex was prepared at room temperature. Biodistribution and scintigraphic imaging studies with ¹⁷⁰Tm-EDTMP complex were performed in normal Wistar rats. Preliminary dosimetric estimation was made using the data to adjudge the suitability of ¹⁷⁰Tm-EDTMP for bone pain palliation.Results¹⁷⁰Tm was produced with a specific activity of 6.36 GBq/mg and radionuclidic purity of 100%. The ¹⁷⁰Tm-EDTMP was prepared with high radiochemical purity (>99%) and the complex exhibited satisfactory in vitro stability. Biodistribution and imaging studies showed good skeletal accumulation (50–55% of the injected activity) with insignificant uptake in any other vital organ/tissue. Activity was observed to be retained in skeleton until 60 days post-injection demonstrating that ¹⁷⁰Tm-EDTMP exhibits good bone-seeking properties with long retention. It is predicted that a dose of ～0.5 μGy/MBq is accrued to red bone marrow and 4.3 Gy/MBq is delivered to the skeleton.Conclusion¹⁷⁰Tm-EDTMP shows promising biodistribution features, encouraging dosimetric values and warrants further investigation in order to develop it as a bone pain palliative radiopharmaceutical. Despite the relatively long half-life (128.4 days) of ¹⁷⁰Tm, ¹⁷⁰Tm-EDTMP could be explored as a cost-effective alternative to ⁸⁹SrCl₂.     

Synthesis of S-[13N]nitrosoglutathione (13N-GSNO) as a new potential PET imaging agent

In the present paper, a fast and reproducible method for the synthesis of S-[¹³N]nitrosoglutathione is reported for the first time. The labeling strategy is based on the production of [¹³N]NO₃⁻ via the ¹⁶O(p,α)¹³N nuclear reaction in water, as opposed to the standardized production of [¹³N]NH₄⁺ in 2 mM aqueous ethanol. Following the reduction of [¹³N]NO₃⁻ to [¹³N]NO₂⁻, the reaction with glutathione in the presence of hydrochloric acid led to the desired radiotracer with a good radiochemical yield (24.2±2.0% end of synthesis, n=5) in a short production time (3 min from the end of bombardment).     

Excitation functions of proton induced nuclear reactions on 85Rb

Excitation functions for the (p, xn) (x=3−5), (p, pxn) (x=1−4) and (p, α3n) reactions on ⁸⁵Rb with 14–70 MeV protons have been measured by means of the activation method. Enriched ⁸⁵RbCl targets were irradiated with energy-analyzed protons from the AVF cyclotron at Osaka University. Disintegration rates of product nuclides were obtained from intensities of selected γ-rays with calibrated Ge(Li) detectors. Thick target yields of ⁸¹Rb for medical use and other radioactive products were calculated from measured excitation functions. The calculated thick target yield of ⁸¹Rb was 31.2 mCi μA⁻¹ h⁻¹ at E_p=70 MeV. The thick target yield of ⁸¹Rb chemically separated from ⁸¹Sr, by the reaction ⁸⁵Rb(p, 5n)⁸¹Sr(β⁺, EC)⁸¹Rb, was obtained to be 2.3 mCi μA⁻¹ h⁻¹ at 96.4 min.     

Synthesis and characterization of [76Br]-labeled high-affinity A3 adenosine receptor ligands for positron emission tomography

IntroductionBromine-76-radiolabeled analogues of previously reported high-affinity A₃ adenosine receptor (A₃AR) nucleoside ligands have been prepared as potential radiotracers for positron emission tomography.MethodsThe radiosyntheses were accomplished by oxidative radiobromination on the N⁶-benzyl moiety of trimethyltin precursors. Biodistribution studies of the kinetics of uptake were conducted in awake rats.ResultsWe prepared an agonist ligand {[⁷⁶Br](1′S,2′R,3′S,4′R,5′S)-4′-{2-chloro-6-[(3-bromophenylmethyl)amino]purin-9-yl}-1′-(methylaminocarbonyl)bicyclo[3.1.0]hexane-2′,3′-diol (MRS3581)} in 59% radiochemical yield with a specific activity of 19.5 GBq/μmol and an antagonist ligand {[⁷⁶Br](1′R,2′R,3′S,4′R,5′S)-4′-(6-(3-bromobenzylamino)-2-chloro-9H-purin-9-yl)bicyclo[3.1.0]hexane-2′,3′-diol (MRS5147)} in 65% radiochemical yield with a specific activity of 22 GBq/μmol. The resultant products exhibited the expected high affinity (K_i～0.6 nM) and specific binding at the human A₃AR in vitro. Biodistribution studies in the rat showed uptake in the organs of excretion and metabolism. The antagonist MRS5147 exhibited increasing uptake in testes, an organ that contains significant quantities of A₃AR, over a 2-h time course, which suggests the presence of a specific A₃AR retention mechanism.ConclusionWe were able to compare uptake of the [⁷⁶Br]-labeled antagonist MRS5147 to [⁷⁶Br]agonist MRS3581. The antagonist MRS5147 shows increasing uptake in the testes, an A₃AR-rich tissue, suggesting that this ligand may have promise as a molecular imaging agent.     

Rapid determination of Sr impurities in freshly “generator eluted” Y for radiopharmaceutical preparation

⁹⁰Y is one of the most useful radionuclides for radioimmunotherapeutic applications and has a half-life (t_1/2=64.14 h) suitable for most therapeutic applications, beta particles of high energy and decays to a stable daughter. It is significant that ⁹⁰Y is available conveniently and inexpensively from a radionuclide “generator” by decay of its parent, ⁹⁰Sr. Nevertheless, current and planned clinical applications with [⁹⁰Y] labelled compounds employ activity levels that cannot be readily obtained from an in-house generator, but from commercial sources. We have evaluated Eichrom's Sr-resin, either as an “in-house” generator or as a fast QC method for analysis of ⁹⁰Y solutions.In particular, for the development as a generator, we investigated the percentage of the radio-Sr in the first 8 M HNO₃ eluate: in this fraction the concentration of ⁹⁰Sr must be smaller than 10⁻⁵% (recommendations of the International Commission on Radiological Protection). For evaluation as a rapid QC method, we analyzed the concentration of ⁹⁰Y in all the fractions containing “only” radio-Sr: ⁹⁰Y should not be present in these eluates. After the collection of β⁻ and γ spectra and analysis of them, we concluded that commercial Sr-resin minicolumn cannot give us the results expected; we developed an in-house system loaded with 4 mL of Sr-resin which gave better results as a generator and a rapid QC method.     

Production of [13N]NH3 with ultra-high specific activity

Aqueous solutions of [¹³N]NH₃ were synthesized according to well-known methods using the ¹⁶O(p, α)¹³N reaction under conditions rendering the smallest possible amount of nitrogen-contaminants. The specific activities and radiochemical yields were measured. Factors, affecting the specific activity of [¹³N]NH₃, were investigated using radio-ionchromatography. The achieved specific activities (GBq/μmol) and radiochemical yields (GBq) of [¹³N]NH₃ were 14±2.8 and 0.3±0.1 (TiCl₃ method)1, 590±200 and 5.4±1.1 (DeVarda's Alloy method), 5500±500 and 12.7±0.1 (ethanol method), and 6200±2700 and 2.8±0.3 (hydrogen method, 3 bar), respectively at 15 μA for 20 min irradiation (1; 5 μA, 5 min irradiation). More than 70% of the N-13 generated with the hydrogen method was of the chemical form [¹³N]N₂.