Characteristics of Bremsstrahlung emissions of (177)Lu, (188)Re, and (90)Y for SPECT/CT quantification in radionuclide therapy.

PURPOSE: Beta particles emitted by radioisotopes used in targeted radionuclide therapies (TRT) create Bremsstrahlung (BRS) which may affect SPECT quantification when imaging these isotopes. The purpose of the current study was to investigate the characteristics of Bremsstrahlung produced in tissue by three ß-emitting radioisotopes used in TRT. METHODS: Monte Carlo simulations of (177)Lu, (188)Re, and (90)Y sources placed in water filled cylinders were performed. BRS yields, mean energies and energy spectra for (a) all photons generated in the decays, (b) photons that were not absorbed and leave the cylinder, and (c) photons detected by the camera were analyzed. Next, the results of simulations were compared with those from experiments performed on a clinical SPECT camera using same acquisition conditions and phantom configurations as in simulations. RESULTS: Simulations reproduced relatively well the shapes of the measured spectra, except for (90)Y which showed an overestimation in the low energy range. Detailed analysis of the results allowed us to suggest best collimators and imaging conditions for each of the investigated isotopes. Finally, our simulations confirmed that the BRS contribution to the energy spectra in quantitative imaging of (177)Lu and (188)Re could be ignored. CONCLUSIONS: For (177)Lu and (188)Re, BRS contributes only marginally to the total spectra recorded by the camera. Our analysis shows that MELP and HE collimators are the best for imaging these two isotopes. For (90)Y, HE collimator should be used.

188Re-ZHER2:V2, a promising affibody-based targeting agent against HER2-expressing tumors: preclinical assessment.

UNLABELLED: Affibody molecules are small (7 kDa) nonimmunoglobulin scaffold proteins with favorable tumor-targeting properties. Studies concerning the influence of chelators on biodistribution of (99m)Tc-labeled Affibody molecules demonstrated that the variant with a C-terminal glycyl-glycyl-glycyl-cysteine peptide-based chelator (designated ZHER2:V2) has the best biodistribution profile in vivo and the lowest renal retention of radioactivity. The aim of this study was to evaluate (188)Re-ZHER2:V2 as a potential candidate for radionuclide therapy of human epidermal growth factor receptor type 2 (HER2)-expressing tumors. METHODS: ZHER2:V2 was labeled with (188)Re using a gluconate-containing kit. Targeting of HER2-overexpressing SKOV-3 ovarian carcinoma xenografts in nude mice was studied for a dosimetry assessment. RESULTS: Binding of (188)Re-ZHER2:V2 to living SKOV-3 cells was demonstrated to be specific, with an affinity of 6.4 ± 0.4 pM. The biodistribution study showed a rapid blood clearance (1.4 ± 0.1 percentage injected activity per gram [%ID/g] at 1 h after injection). The tumor uptake was 14 ± 2, 12 ± 2, 5 ± 2, and 1.8 ± 0.5 %IA/g at 1, 4, 24, and 48 h after injection, respectively. The in vivo targeting of HER2-expressing xenografts was specific. Already at 4 h after injection, tumor uptake exceeded kidney uptake (2.1 ± 0.2 %IA/g). Scintillation-camera imaging showed that tumor xenografts were the only sites with prominent accumulation of radioactivity at 4 h after injection. Based on the biokinetics, a dosimetry evaluation for humans suggests that (188)Re-ZHER2:V2 would provide an absorbed dose to tumor of 79 Gy without exceeding absorbed doses of 23 Gy to kidneys and 2 Gy to bone marrow. This indicates that future human radiotherapy studies may be feasible. CONCLUSION: (188)Re-ZHER2:V2 can deliver high absorbed doses to tumors without exceeding kidney and bone marrow toxicity limits.

Assessment of the best N(3-) donors in preparation of [M(N)(PNP)]-based (M=(99m)Tc-; (188)Re) target-specific radiopharmaceuticals: Comparison among succinic dihydrazide (SDH), N-methyl-S-methyl dithiocarbazate (HDTCZ) and PEGylated N-methyl-S-methyl dithiocarbazate (HO2C-PEG600-DTCZ).

Succinic dihydrazide (SDH), N-methyl-S-methyl dithiocarbazate (HDTCZ) and PEGylated N-methyl-S-methyl dithiocarbazate (HO2C-PEG600-DTCZ) are nitrido nitrogen atom donors employed for the preparation of nitride [M(N)]-complexes (M=(99m)Tc and (188)Re). This study aims to compare the capability and the efficiency of these three N(3-) group donors, in the preparation of [M(N)PNP]-based target-specific compounds (M=(99m)Tc, (188)Re; PNP=aminodiphosphine). For this purpose, three different kit formulations (SDH kit; HO2C-PEG600-DTCZ kit; HDTCZ kit) were assembled and used in the preparation of [M(N)(cys~)(PNP3)](0/+) complexes (cys~=cysteine derivate ligands). For each formulation, the radiochemical yield (RCY) of the [M(N)(~cys)(PNP3)] compounds, was determined by HPLC. The deviation of the percentage of RCY, due to changes in concentration of the N(3-) donors and of the exchanging ligand, was determined. For (99m)Tc, data clearly show that HDTCZ is the most efficient donor of N(3-); however, SDH is the most suitable nitrido nitrogen atom donor for the preparation of [(99m)Tc(N)(PNP)]-based target-specific agents with high specific activity. When HO2C-PEG600-DTCZ or HDTCZ are used in N(3-) donation, high amounts of the exchanging ligand (10(-4)M) were required for the formation of the final complex in acceptable yield. The possibility to use microgram amounts of HDTCZ also in [(188)Re(N)] preparation (0.050mg) reduces its ability to compete in ligand exchange reactions, minimizing the quantity of chelators required to obtain the final complex in high yield. This finding can be exploit for increasing the radiolabeling efficiency in [(188)Re(N)]-radiopharmaceutical preparations compared to the previously reported HDTCZ-based procedure, notwithstanding a purification process could be necessary to improve the specific activity of the complexes.

Magnetic and transport properties of PrRhSi3.

We have investigated the magnetic and transport properties of a noncentrosymmetric compound PrRhSi3 by dc magnetic susceptibility χ(T), isothermal magnetization M(H), thermoremanent magnetization M(t), specific heat Cp(T), electrical resistivity ρ(T,H) and muon spin relaxation (µSR) measurements. At low fields χ(T) shows two anomalies near 15 and 7 K with an irreversibility between ZFC and FC data below 15 K. In contrast, no anomaly is observed in Cp(T) or ρ(T) data. M(H) data at 2 K exhibit very sharp increase below 0.5 T and a weak hysteresis. M(t) exhibits very slow relaxation, typical for a spin-glass system. Even though the absence of any anomaly in Cp(T) is consistent with the spin-glass type behavior, there is no obvious origin of spin-glass behavior in this structurally well ordered compound. The crystal electric field (CEF) analysis of Cp(T) data indicates a CEF-split singlet ground state lying below a doublet at 81(1) K and a quasi-triplet at 152(2) K. The ρ(T) data indicate a metallic behavior, and ρ(H) exhibits a very high positive magnetoresistance, as high as ~300% in 9 T at 2 K. No long range magnetic order or spin-glass behavior was detected in a µSR experiment down to 1.2 K.

Study of magnetic nanovectors by Wet-STEM, a new ESEM mode in transmission.

Many nanovectors used for therapy (drug targeting, radiation therapy) or diagnostic such as Magnetic Resonance Imaging (MRI) have a composite structure consisting of an organic core or organic coverage encapsulating magnetic nanoparticles and they are commonly dispersed in liquid suspensions for intravenous injection. Here is presented the application of a new Environmental Scanning Electron Microscopy (ESEM) mode in transmission, so called Wet-STEM, for transmission imaging of droplets of such suspensions. This is illustrated by Wet-STEM images from PLLA/Re nanospheres (about 100-300 nm in diameter) loaded with magnetite nanoparticles (about 10 nm in diameter) and from iron oxide core (about 5 nm in size) MRI contrast agents, both examples in aqueous suspensions. It is shown that the Wet-STEM mode allows both the collective behavior of such nanovectors in suspension to be characterized and the inner composite structure of individual vectors to be revealed. Such experimental results are discussed by comparison with Monte Carlo computer simulations of the distribution of the electrons scattered through the samples in rather large solid angles (between 20° and 47°) corresponding to the detection conditions.

Assessment of macrocyclic triamine ligands as synthons for organometallic 99mTc radiopharmaceuticals.

In a search of coordination molecules suitable to the fac-{(99m)Tc(CO)3}(+) core as a synthon for (99m)Tc-radiopharmaceuticals, nonradioactive rhenium complexes of two macrocyclic triamine compounds with different chelate ring structures, 1,4,7-triazacyclononane (9N3) and 1,5,9-triazacyclododecane (12N3), were synthesized and characterized. (99m)Tc-labeled 9N3 and 12N3 compounds were also prepared using [(99m)Tc(OH 2)3(CO)3](+) and were characterized by both in vitro and in vivo studies. 9N3 produced a single rhenium complex, whereas 12N3 generated two major complexes. The crystallographic data and infrared absorption wavenumber assigned to the C-O stretch suggested that the coordination geometry of 9N3 would be more suitable to fac-{Re(CO)3}(+) than that of 12N3. In contrast, both 9N3 and 12N3 provided a single (99m)Tc-labeled compound. However (99m)Tc-labeled 9N3 exhibited higher stability than (99m)Tc-labeled 12N3 in rat plasma and in the presence of histidine at an elevated temperature. In biodistribution studies, both (99m)Tc-labeled compounds did not show any specific accumulation of radioactivity in any organs except for the excretory organs such as the liver and kidney. These findings showed that 9N3 would constitute a macrocyclic chelating molecule of choice to prepare (99m)Tc radiopharmaceuticals using a fac-{(99m)Tc(CO)3}(+) core.

Assessment of 186Re chelate-conjugated bisphosphonate for the development of new radiopharmaceuticals for bones.

INTRODUCTION: The preferable pharmacokinetics of rhenium-186 (186Re)-monoaminemonoamidedithiol-conjugated or 186Re-mercaptoacetyltriglycine-conjugated bisphosphonates (BPs) suggested that the molecular design would be applicable to other radionuclides such as 68Ga, 99mTc, 153Sm and 177Lu. In this study, a key factor affecting the pharmacokinetics of a chelate-conjugated BP was investigated to estimate the validity and the applicability of molecular design. METHODS: Chemically inert and well-characterized tricarbonyl[186Re][(cyclopentadienylcarbonyl amino)-acetic acid]rhenium ([186Re]CpTR-Gly) was conjugated with 3-amino-1-hydroxypropylidene-1,1-bisphosphonate and purified by high-performance liquid chromatography (HPLC) to prepare [186Re](1-{3-[tricarbonyl(cyclopentadienylcarbonyl amino)-acetylamido]-1-hydroxy-1-phosphono-propyl}-phosphonic acid)rhenium ([186Re]CpTR-Gly-APD). Plasma stability, plasma protein binding, hydroxyapatite (HA) binding and the pharmacokinetics of [186Re]CpTR-Gly-APD were compared with those of 186Re 1-hydroxyethylidene-1,1-diphosphonate (HEDP). The effect of HEDP coadministration and preadministration on the pharmacokinetics of [186Re]CpTR-Gly-APD was also determined. RESULTS: The HPLC-purified [186Re]CpTR-Gly-APD showed higher plasma stability, higher HA binding, higher bone accumulation and lower plasma protein binding than did 186Re-HEDP. However, HA binding of [186Re]CpTR-Gly-APD decreased to levels slightly higher than that of 186Re-HEDP at similar HEDP concentrations. Bone accumulation of [186Re]CpTR-Gly-APD also decreased to levels similar to that of 186Re-HEDP when [186Re]CpTR-Gly-APD was coinjected with HEDP equivalent to that in 186Re-HEDP. In contrast, HEDP pretreatment did not impair bone accumulation of the two 186Re-labeled compounds. However, a delay in blood clearance and an increase in renal radioactivity levels were observed particularly with 186Re-HEDP. CONCLUSIONS: Although 186Re-HEDP possessed HA binding and bone accumulation similar to those of [186Re]CpTR-Gly-APD, the specific activity of 186Re-labeled BPs was found to play a crucial role in bone accumulation and blood clearance. Thus, the molecular design of chelate-conjugated BP would be useful for the development of bone-seeking radiopharmaceuticals with a variety of radionuclides by selecting chelating molecules that provide high specific activities.

Preparation of (188) Re-labeled paper for treating skin cancer.

For homogeneous delivery of beta radiation to skin cancer, we developed a simple method for preparing (188) Re-labeled nitrocellulose paper. The homogeneity and stability of the labeled paper were investigated. Absorbed dose estimates were calculated using the Monte-Carlo method. A 74-MBq (188) Re-labeled paper with 1-cm diameter delivered 147.2 Gy up to 1-mm depth after 2-h irradiation. Animal experiments on tumor-bearing mice showed that 50 Gy is an adequate dose for treating skin cancer. Tumors disappeared 7 days after irradiation in all the groups irradiated by 50 or 100 Gy. The (188) Re-labeled paper provided a convenient, economical, effective, and non-invasive method of treating skin cancer.