Neil V. Jarvis

Preclinical Evaluation of 68Ga-Labeled 1,4,7-Triazacyclononane-1,4,7-Triacetic Acid-Ubiquicidin as a Radioligand for PET Infection Imaging

Antimicrobial peptides such as ubiquicidin (UBI) are believed to differentiate between mammalian and bacterial or fungal cells. 99mTc-UBI29-41 was previously tested for detecting infection in humans using SPECT. For the present study, the UBI fragment UBI29-41 (TGRAKRRMQYNRR) was conjugated to 1,4,7-triazacyclononane-triacetic acid (NOTA), radiolabeled with 68Ga, and investigated in a rabbit infection model. Methods: 68Ga was obtained from a 1.85-GBq 68Ge/68Ga generator. New Zealand White rabbits were anesthetized with ketamine/medetomidine before tracer administration and placed in a clinical PET/CT scanner. 68Ga-1,4,7-triazacyclononane-1,4,7-triacetic-acid-ubiquicidin29-41 (68Ga-NOTA-UBI29-41) was formulated in saline solution, and 101 ± 41 MBq were administered intravenously. The tracer distribution was studied by PET/CT imaging in animals (a) that were healthy, (b) bearing muscular Staphylococcus aureus infections and turpentine oil-induced muscular inflammations, and (c) bearing ovalbumin-induced lung inflammations. Static PET/CT imaging was performed at different time intervals up to 120 min after injection. For calculation of target-to-nontarget ratios, standardized uptake values were normalized against healthy thigh muscle, representing nontargeted tissue. Results: PET/CT images of healthy animals showed predominant distribution in the kidneys, liver, and bladder; heart and spleen showed moderate, declining uptake, only. The biologic half-life in blood was 29 min. Urinary accumulation of 68Ga-NOTA-UBI29-41 peaked at 3.8 ± 0.91 percentage injected dose per gram (%ID) at 120 min, and 88 ± 5.2 %ID was recovered in total urine. 68Ga-NOTA-UBI29-41 imaging in (b) selectively visualized the muscular infection site and was differentiated from sterile inflammatory processes. Standardized uptake value ratios for muscles (infected/inflamed) were 2.9 ± 0.93, 2.9 ± 0.50, 3.5 ± 0.86, and 3.8 ± 0.90 at 5, 30, 60, and 90 min after injection, respectively. Rabbit lungs with asthma showed insignificant uptake. Conclusion: 68Ga-NOTA-UBI29-41 was strongly localized in bacteria-infected areas and minimally detected in a sterile inflammation area in rabbit muscles. The findings propose this compound to be an excellent first-line PET/CT tracer to allow the distinguishing of infection from inflammation.

The degradation of monazite Implications for the mobility of rare-earth and actinide elements during low-temperature alteration

Monazite is an important economic source of thorium, the rare-earth elements and uranium. This and its chemically inert nature has led to speculation that artificial phosphate-based matrices similar in composition to monazite may prove useful as wasteforms for high-level radioactive waste. In order to assess the long-term degradation behaviour of monazite, an integrated geological, hydrogeological and mineralogical study was undertaken at the Steenkampskraal monazite mine, South Africa. Steenkampskraal is among the richest monazite ore bodies in the world comprising up to 45 weight % rare-earth oxides, 8.8% thorium oxides and 600 ppm uranium. Optical and electron-microprobe analyses of the ore reveal distinctive alteration patterns with uranium appearing to be lost preferentially. The heavy rare earths are also preferentially removed from the ore, giving rise to a marked fractionation in altered grains. Thorium, although leached, is re-concentrated together with the heavier rare-earth elements in microcrystalline silicate and oxide alteration products within the host rock. The implications for waste encapsulation are discussed from the perspective of potential groundwater transport away from the source.

Metal-ion speciation in blood plasma incorporating the tetraphosphonate, N,N-dimethylenephosphonate-1-hydroxy-4-aminopropilydenediphosphonate (APDDMP), in therapeutic radiopharmaceuticals

In a quest for more effective radiopharmaceuticals for pain palliation of metastatic bone cancer, this paper relates results obtained with 166Ho and 153Sm complexed to the bone seeking phosphonate, N,N-dimethylenephosphonate-1-hydroxy-4-aminopropylidenediphosphonate (APDDMP). APDDMP is synthesised from the known bone cancer pain palliation agent 1-hydroxy-3-aminopropylidenediphosphonate (APD) and was complexed to lanthanide trivalent metal ions. This work is performed to utilise the idea that the energetic beta-particle emitter, 166 Ho, coupled with phosphonate ligands such as APD and APDDMP could afford a highly effective radiopharmaceutical in the treatment of bone cancer. Complex-formation constants of APDDMP with the important blood plasma metal-ions, Ca2+, Mg2+, and Zn2+ and the trivalent lanthanides Ho3+ and Sm3+ were measured by glass electrode potentiometry at 37 degrees C and I = 150 mM. Blood plasma models were constructed using the computer code ECCLES and the results compared with those gathered from animal tests. The 166Ho-APDDMP complex was found to have little liver or bone uptake while 153Sm-APDDMP had a moderate bone uptake. This was primarily due to the high affinity of APDDMP for Ca(II). Clinical observations could be explained by the blood plasma modelling.

Metal-ion speciation in blood plasma incorporating the bisphosphonate, 1-hydroxy-4-aminopropilydenediphosphonate (APD), in therapeutic radiopharmaceuticals.

In the quest for more effective pain palliation radiopharmaceuticals for metastatic bone cancer, this paper relates results obtained with 166Ho complexed to the bone-seeking bisphosphonate, 1-hydroxy-4-aminopropililydenediphosphonate (APD). APD is itself a bone cancer pain palliation agent and this work was therefore driven by the idea that the energetic beta-particle emitter, 166Ho, coupled with APD could afford a highly effective radiopharmaceutical in the treatment of bone cancer. Complex-formation constants for important blood plasma metal-ions were measured by potentiometry or polarography at 37 degrees C and I = 150 mmol dm-3. The latter technique was used for systems where precipitates formed at ligand-to-metal ratios appropriate for potentiometry. For trivalent lanthanides, neither electrochemical technique could be used. Animal tests showed that the 166Ho-APD complex was taken up primarily by the liver due to precipitation or colloid formation.

A potentiometric and differential pulse polarographic study of CdII with 1-hydroxyethylenediphosphonic acid

The complexation of the ligand 1-hydroxyethylenediphosphonic acid (HEDP) with Cd II was studied by differential pulse polarography (DPP) and glass electrode potentiometry (GEP) at fixed total ligand to total metal concentration ratios and varied pH values. Labile and non-labile metal complexes were analysed simultaneously by the use of a polarographic experimental complex formation curve (ECFC) and the calculated complex formation curve (CCFC). Complex formation curves were used for modelling of the metal‐ligand system and the refinement of stability constants. The ECFC, in which experimental parameters of only labile DPP peak are included (a shift in the peak potential and a variation in the peak height) appears to be a characteristic function for a full metal‐ligand model (labile and non-labile parts of a metal‐ligand system). The CCFC is a theoretical curve calculated for the assumed metal‐ligand model from mass-balance equations. The final model of metal species formed is the one, which is confirmed by these two experimental techniques, and for which stability constants of metal complexes obtained from DPP and GEP differ the least. Six cadmium complexes M(H4L), M(H2L), M2L, ML (all labile), ML2 (non-labile), and ML(OH) (labile) and their stability constants as log found from DPP 25.040.06, 19.560.02, 12.670.03, 7.260.02, 10.390.06 and 10.930.04, respectively, are reported. Results obtained from GEP are also reported and they differ from polarographic results only within the experimental errors typical for these techniques. # 1999 Elsevier Science B.V. All rights reserved.

A thermodynamic approach, using speciation studies, towards the evaluation and design of bone-seeking radiopharmaceuticals as illustrated for 117mSn(II)-PEI-MP

Blood plasma modeling has proved effective in the evaluation of clinical observations recorded for baboon and rat tests with 153Sm- ethylenediaminetetraphosphonic acid (EDTMP) as well as for 166Ho-EDTMP. In the search for a cure for metastatic bone cancer, 117mSn with its conversion electrons of discrete energies shows low bone marrow toxicity, providing the opportunity to increase the administered dose. Selective accumulation in lesions would capitalize on this advantage. The 10-30 kDa fraction of the water-soluble polymer polyethyleneimine, functionalized with methylene phosphonate groups (PEI-MP) and labeled with 99mTc, has shown selective uptake into bone tumours. This paper relates the speciation of Sn(II)-PEI-MP and other known 117mSn(II) containing bone-seeking radiopharmaceuticals in blood plasma. Apparent formation constants for the complexation of SnII with PEI-MP, DTPA, HEDP and other important blood plasma ligands were measured potentiometrically or estimated by linear free energy relationships (LFER). These data were added to the ECCLES database in order to construct a blood plasma model for SnII. From this model it is predicted that SnII will remain bound to the polymer (PEI-MP) in blood plasma and therefore, have only slight reticuloendothelial uptake. Preliminary primate studies indeed proved that the complex between SnII and PEI-MP remains intact in blood plasma, which is consistent with the observation for PEI-MP labeled with 99mTc. From these data, it was also possible to explain in retrospect the lower bone uptake, the slow blood clearance and the liver uptake of the agents 117mSn(II) DTPA and 117mSn(II) HEDP agents as reported in the literature.

Metal-ion speciation in blood plasma incorporating the water-soluble polymer, polyethyleneimine functionalised with methylenephosphonate groups, in therapeutic radiopharmaceuticals

Summary A water-soluble polymer, polyethyleneimine functionalised with methylene phosphonate groups (PEI-MP) and labelled with 99mTc, has shown selective uptake into bone tumours. Apparent formation constants for the complexation of important blood plasma metal-ions and metal-ions of radionuclides used in therapeutic radiopharmaceuticals (excluding Tc) with PEI-MP were measured potentiometrically. These were added to the ECCLES data base in order to construct a blood plasma model for PEI-MP. From this model it could be predicted that the polymer would not deliver the therapeutic radionuclides 153Sm, 166Ho, 212Pb, 213Pb and 89Sr to bone. This was clinically verified for 153Sm. However good uptake of 99mTc-PEI-MP could be demonstrated in dogs. Due to the similar chemistry of Re as compared to Tc, it can be expected that PEI-MP labelled with 186Re or 188Re could result in effective therapeutic radiopharmaceuticals for bone cancer.

EVALUATION OF A DIETHANOLAMINE CHELATING RESIN USING TWO-PHASE POTENTIOMETRY

ABSTRACT The synthesis of a polystyrene resin functionalised with diethanolamine is described. Protonation of the resin and complexation of Pb(II), Cd(II), Hg(II), UO2 2+, Fe(III), Ca(n) and Nd(III) were studied using two-phase potentiometry. From these experiments, apparent formation constants could be calculated and distribution curves obtained. Predictions as to metal ion separations were then possible. Batch experiments with Eu(III) and Pu(IV) were also performed as well as a column experiment for Pb(II) and Ca(II) to test selectivity. The resin shows selectivity towards metal ions that are large and/or have a good affinity for nitrogen donor ligands. Metal ions susceptible to hydrolysis are well complexed by the resin due to its ability to suppress hydrolysis.

Metal-ion speciation in blood plasma as a tool for elucidating the in vivo behaviour of radiopharmaceuticals containing 153Sm and 166Ho

In order to elucidate the in vivo behaviour of SmIII and HoIII, complex-formation constants for a range of blood plasma metal ions as well as these with the octaanion ethylenediaminetetramethylenephosphonate (edtmp) have been measured at 37 °C and l= 150 mmol dm–3. The speciation in the absence and presence of edtmp and/or transferrin was calculated by the program ECCLES and is used to explain the apparently anomalous discrepancies in the uptake of the two metals by bone in a baboon model. The computer results predicted the mobilisation of ZnII and, when tested clinically, it was found that edtmp indeed removes this ion from blood plasma.

Recoil and conversion electron considerations of the 166Dy/166Ho in vivo generator

Abstract The use of radionuclides as potential therapeutic radiopharmaceuticals is increasingly investigated. An important aspect is the delivery of the radionuclide to the target, i.e. the radionuclide is not lost from the chelating agent. For in vivo generators, it is not only the log K of complexation between the metal ion and the chelator that is important, but also whether the daughter radionuclide stays inside the chelator after decay of the parent radionuclide. In our previous work, we showed that the classical recoil effect is only applicable for decays with a Q value higher than 0.6 MeV (in the atomic mass range around 100). However, Zhernosekov et al. [1] published a result for140Nd/140Pr (Q = 0.222 MeV) which indicated that >95% of the daughter (140Pr) was lost by a DOTA chelator upon decay of140Nd. The authors ascribed this to the & ldquo;post-effect”. Their experiment was repeated with the166Dy/166Ho generator to ascertain whether our calculations were correct. It was found that 72% of the daughter (166Ho) was liberated from the DOTA chelator, indicating that the “post effect” does exist in contrast to our recoil calculations. Upon further investigation, we determined that one should not only consider recoil energy levels but also the mode of decay which was able to explain the partial recoil found for166Dy/166Ho. It is concluded for the166Dy/166Ho system that the low recoil energy of the daughter nucleus166Ho is not a sufficient reason to rule out release of the nuclide from chelators. On the other hand, we found that the ratio of the166Ho that gets released corresponds to the ratio of relaxation of Ho atoms via the Auger process.