Elisabeth Oehlke

44gSc production using a water target on a 13 MeV cyclotron

INTRODUCTION Access to promising radiometals as isotopes for novel molecular imaging agents requires that they are routinely available and inexpensive to obtain. Proximity to a cyclotron center outfitted with solid target hardware, or to an isotope generator for the metal of interest is necessary, both of which can introduce significant hurdles in development of less common isotopes. Herein, we describe the production of ⁴⁴Sc (t1/2=3.97 h, Eavg,β⁺=1.47MeV, branching ratio=94.27%) in a solution target and an automated loading system which allows a quick turn-around between different radiometallic isotopes and therefore greatly improves their availability for tracer development. Experimental yields are compared to theoretical calculations. METHODS Solutions containing a high concentration (1.44-1.55g/mL) of natural-abundance calcium nitrate tetrahydrate (Ca(NO₃)2·4 H₂O) were irradiated on a 13MeV proton-beam cyclotron using a standard liquid target. (44g)Sc was produced via the ⁴⁴Ca(p,n)(44g)Sc reaction. RESULTS (44g)Sc was produced for the first time in a solution target with yields sufficient for early radiochemical studies. Saturation yields of up to 4.6 ± 0.3 MBq/μA were achieved using 7.6 ± 0.3 μA proton beams for 60.0 ± 0.2 minutes (number of runs n=3). Experimental data and calculation results are in fair agreement. Scandium was isolated from the target mixture via solid-phase extraction with 88 ± 6% (n=5) efficiency and successfully used for radiolabelling experiments. The demonstration of the production of ⁴⁴Sc in a liquid target greatly improves its availability for tracer development.

Influence of metal ions on the 68Ga-labeling of DOTATATE

The influence of metal cations (Fe³⁺, Fe²⁺, In³⁺, Cu²⁺, Ca²⁺, Al³⁺, Co²⁺, Lu³⁺, Ni²⁺, Pb²⁺, Ti⁴⁺, Y³⁺, Yb³⁺, Zn²⁺, and Zr⁴⁺) on the radiolabeling yield of [⁶⁸Ga(DOTATATE)] was evaluated. Our most important observation was that, within our experimental limit, the metal ion/ligand ratio plays a critical role on the influence of most metal ions. More in-depth studies, with Cu²⁺ and Fe³⁺, revealed that reaction temperature and concentration changes have little effect, but speciation changes with pH are crucial. Furthermore, we found that [⁶⁸Ga(DOTATATE)] is stable in the presence of high concentrations of Fe³⁺, Zn²⁺ and Pb²⁺, but transmetalates with Cu²⁺ at 95°C.

Aryl and NHC Compounds of Technetium and Rhenium

Air- and water-stable phenyl complexes with nitridotechnetium(V) cores can be prepared by straightforward procedures. [TcNPh(2)(PPh(3))(2)] is formed by the reaction of [TcNCl(2)(PPh(3))(2)] with PhLi. The analogous N-heterocyclic carbene (NHC) compound [TcNPh(2)(HL(Ph))(2)], where HL(Ph) is 1,3,4-triphenyl-1,2,4-triazol-5-ylidene, is available from (NBu(4))[TcNCl(4)] and HL(Ph) or its methoxo-protected form. The latter compound allows the comparison of different Tc-C bonds within one compound. Surprisingly, the Tc chemistry with such NHCs does not resemble that of corresponding Re complexes, where CH activation and orthometalation dominate.

Production of Y-86 and other radiometals for research purposes using a solution target system.

INTRODUCTION Diagnostic radiometals are typically obtained from cyclotrons by irradiating solid targets or from radioisotope generators. These methods have the advantage of high production yields, but require additional solid target handling infrastructure that is not readily available to many cyclotron facilities. Herein, we provide an overview of our results regarding the production of various positron-emitting radiometals using a liquid target system installed on a 13 MeV cyclotron at TRIUMF. Details about the production, purification and quality control of (89)Zr, (68)Ga and for the first time (86)Y are discussed. METHODS Aqueous solutions containing 1.35-1.65 g/mL of natural-abundance zinc nitrate, yttrium nitrate, and strontium nitrate were irradiated on a 13 MeV cyclotron using a standard liquid target. Different target body and foil materials were investigated for corrosion. Production yields were calculated using theoretical cross-sections from the EMPIRE code and compared with experimental results. The radioisotopes were extracted from irradiated target material using solid phase extraction methods adapted from previously reported methods, and used for radiolabelling experiments. RESULTS We demonstrated production quantities that are sufficient for chemical and biological studies for three separate radiometals, (89)Zr (Asat = 360 MBq/μA and yield = 3.17 MBq/μA), (86)Y (Asat = 31 MBq/μA and yield = 1.44 MBq/μA), and (68)Ga (Asat = 141 MBq/μA and yield = 64 MBq/μA) from one hour long irradiations on a typical medical cyclotron. (68)Ga yields were sufficient for potential clinical applications. In order to avoid corrosion of the target body and target foil, nitrate solutions were chosen as well as niobium as target-body material. An automatic loading system enabled up to three production runs per day. The separation efficiency ranged from 82 to 99%. Subsequently, (68)Ga and (86)Y were successfully used to radiolabel DOTA-based chelators while deferoxamine was used to coordinate (89)Zr.

Synthesis and Radiolabelling of DOTA-Linked Glutamine Analogues with 67,68Ga as Markers for Increased Glutamine Metabolism in Tumour Cells

DOTA-linked glutamine analogues with a C6- alkyl and polyethyleneglycol (PEG) chain between the chelating group and the l-glutamine moiety were synthesised and labelled with 67,68Ga using established methods. High yields were achieved for the radiolabelling of the molecules with both radionuclides (>90%), although conversion of the commercially available 67Ga-citrate to the chloride species was a requirement for consistent high radiochemical yields. The generator produced 68Ga was in the [68Ga(OH)4]− form. The 67Ga complexes and the 67Ga complexes were demonstrated to be stable in PBS buffer for a week. Uptake studies were performed with longer lived 67Ga analogues against four tumour cell lines, as well as uptake inhibition studies against l-glutamine, and two known amino acid transporter inhibitors. Marginal uptake was exhibited in the PEG variant radio-complex, and inhibition studies indicate this uptake is via a non-targeted amino acid pathway.

Synthesis, Characterization, and Structures of R3EOTcO3 Complexes (E = C, Si, Ge, Sn, Pb) and Related Compounds

AgTcO(4) reacts with R(3)ECl compounds (E = C, Si, Ge, Sn, Pb; R = Me, (i)Pr, (t)Bu, Ph), (t)Bu(2)SnCl(2), or PhMgCl under formation of novel trioxotechnetium(VII) derivatives. The carbon and silicon derivatives readily undergo decomposition, which was proven by (99)Tc NMR spectroscopy and the isolation of decomposition products such as [TcOCl(3)(THF)(OH(2))]. Compounds [Ph(3)GeOTcO(3)], [(THF)Ph(3)SnOTcO(3)], [(O(3)TcO)Sn(t)Bu(2)(OH)](2), and [(THF)(4)Mg(OTcO(3))(2)] are more stable and were isolated in crystalline form and characterized by X-ray diffraction.

The role of additives in moderating the influence of Fe(III) and Cu(II) on the radiochemical yield of [⁶⁸Ga(DOTATATE)].

[(68)Ga(DOTATATE)] has demonstrated its clinical usefulness. Both Fe(3+) and Cu(2+), potential contaminants in Gallium-68 generator eluent, substantially reduce the radiochemical (RC) yield of [(68)Ga(DOTATATE)] if the metal/ligand ratio of 1:1 is exceeded. A variety of compounds were examined for their potential ability to reduce this effect. Most had no effect on RC yield. However, addition of phosphate diminished the influence of Fe(3+) by likely forming an insoluble iron salt. Addition of ascorbic acid reduced Cu(2+) and Fe(3+) to Cu(+) and Fe(2+) respectively, both of which have limited impact on RC yields. At low ligand amounts (5 nmol DOTATATE), the addition of 30 nmol phosphate (0.19 mM) increased the tolerance of Fe(3+) from 4 nmol to 10 nmol (0.06 mM), while the addition of ascorbic acid allowed high RC yields (>95%) in the presence of 40 nmol Fe(3+) (0.25 mM) and 100 nmol Cu(2+) (0.63 mM). The effect of ascorbic acid was highly pH-dependant, and gave optimal results at pH 3.

Semi-automated system for concentrating 68Ga-eluate to obtain high molar and volume concentration of 68Ga-Radiopharmaca for preclinical applications

INTRODUCTION 68Ga-radiopharmaceuticals are common in the field of Nuclear Medicine to visualize receptor-mediated processes. In contrast to straightforward labeling procedures for clinical applications, preclinical in vitro and in vivo applications are hampered for reasons like e.g. volume restriction, activity concentration, molar activity and osmolality. Therefore, we developed a semi-automatic system specifically to overcome these problems. A difficulty appeared unexpectedly, as intrinsic trace metals derived from eluate (Zn, Fe and Cu) are concentrated as well in amounts that influence radiochemical yield and thus lower molar activity. METHODS To purify Gallium-68 and to reduce the high elution volume of a 68Ga-generator, a NaCl-based method using a column containing PS-H+ was implemented in a low volume PEEK system. Influence on reducing osmolality, acidity and the amount of PS-H+ resin (15-50 mg) was investigated. [68Ga]Ga was desorbed from the PS-H+ resin with acidified 2-5 M NaCl (containing 0.05 M of HCl) and 68Ga-activity was collected. DOTA-TATE was used as a peptide model. All buffers and additives used for labeling were mixed with Chelex 100 (~1 g/50 mL) for >144 h and eventually filtered using a 0.22 μm filter (Millipore). Quantification of metals was performed after labeling by HPLC (UV). RESULTS Gallium-68 activity could be desorbed from PS-H+ cation column with 3 M NaCl, and >60% (120-180 MBq) of [68Ga]Ga was collected in <0.3 mL. Taking into account the used amount of 68Ga-eluate, buffer and other excipients, the overall amount of trace metal per labeling was <1.5 nmol. DOTA-TATE could be labeled with [68Ga]Ga with high radiochemical yield, >99% (ITLC), and a radiochemical purity of >95% (HPLC). CONCLUSION With the here described concentration system and metal purification technique, a low activity containing 68Ga-generator can be used to label DOTA-peptide in preclinical applicable amounts >60 MBq/nmol (40-60 MBq/0.1 mL) and within 20 min.