Vítor H. Alves

Production of copper-64 and gallium-68 with a medical cyclotron using liquid targets

This work describes the production of two clinically relevant metal radioisotopes 64Cu and 68Ga with a medical cyclotron by the irradiation of liquid targets. New results are presented for the implementation of this methodology in a fully automated system, using commercially available equipment. Liquid target solutions containing enriched 64Ni and 68Zn were loaded, bombarded and transferred to synthesis modules where a purified solution containing the desired radiometal is obtained and can then be used to further radiolabeling within only one hour after End-Of-Bombardment (EOB). Typical production runs using enriched material lead to the production of 5 GBq and 6 GBq (0.14 MBq/(μAh ⋅ mg) and 1.5 MBq/(μAh ⋅ mg)) of 64Cu and 68Ga; although the technique can be used to obtain up to 25 GBq and 40 GBq, respectively, by simply scaling up the amount of the enriched material. Purified solutions containing 64Cu and 68Ga were obtained within 30 min after EOB and used to produce 64Cu-ATSM and 68Ga–DOTA–NOC, respectively, with quality parameters suitable for human use.

Cyclotron production of Ga-68 for human use from liquid targets: From theory to practice

A fully automated system for the production of 68Ga based on commercially available cyclotron liquid target and synthesis modules is described. A solution containing enriched 68Zn dissolved in a nitric solution is irradiated in a Cyclone 18/9 IBA cyclotron leading to the production of up to about 25 GBq of 68Ga. The irradiated solution is transferred to a Synthera synthesis module in which 68Ga is separated and purified with a yield superior to 85 % and where further labelling is achieved with yields no inferior to 70 %. The developed and implemented method presents an improved approach for the production of 68Ga-radiopharmaceuticals suitable for human use, in a process that takes less than 2 hours. This technique represents an economically viable alternative to 68Ge/68Ga generators with improved characteristics.

Biophysical characterization and antineoplastic activity of new bis(thiosemicarbazonato) Cu(II) complexes

Aiming to explore alternative mechanisms of cellular uptake and cytotoxicity, we have studied a new family of copper(II) complexes (CuL1-CuL4) with bis(thiosemicarbazone) (BTSC) ligands containing pendant protonable cyclic amines (morpholine and piperidine). Herein, we report on the synthesis and characterization of these new complexes, as well as on their biological performance (cytotoxic activity, cellular uptake, protein and DNA binding), in comparison with the parental CuIIATSM (ATSM=diacetyl-bis(N4-methylthiosemicarbazonate) complex without pendant cyclic amines. The new compounds have been characterized by a range of analytical techniques including ESI-MS, IR spectroscopy, cyclic voltammetry, reverse-phase HPLC and X-ray spectroscopy. In vitro cytotoxicity studies revealed that the copper complexes are cytotoxic, unlike the corresponding ligands, with a similar potency to that of CuATSM. Unlike CuATSM, the new complexes were able to circumvent cisplatin cross-resistance. The presence of the protonable cyclic amines did not lead to an enhancement of the interaction of the complexes with human serum albumin or calf thymus DNA. However, CuL1-CuL4 showed a remarkably augmented cellular uptake compared with CuATSM, as proved by uptake, internalization and externalization studies that were performed using the radioactive congeners 64CuL1-64CuL4. The enhanced cellular uptake of CuL1-CuL4 indicates that this new family of CuIIBTSC complexes deserves to be further evaluated in the design of metallodrugs for cancer theranostics.

Optimisation of synthesis, purification and reformulation of (R)-[N-Methyl- 11 C]PK11195 for in vivo PET imaging studies

Neurodegenerative, inflammatory and neoplastic disorders involve neuroinflammatory reactions in the central nervous system that isolate the damaged tissue and promote im-mune responses by the activation of resident cells of the mono-cytes lineage (microglia). This process involves an overexpression of the 18 kDa translocator protein receptor (TSPO). PK11195 is an isoquinoline carboxamide which binds selectively to this re-ceptor. The (R)-enantiomer radiolabelled with carbon-11 is the most widely used radiotracer for in vivo TSPO imaging with Posi-tron Emission Tomography (PET). We report the optimisation of synthesis, purification and reformulation of (R)-[N-MethyJ-11C]PK11195 by the captive solvent method suitable for use in human PET imaging studies. (R)-[NMethyJ-11C]PK11195 was prepared from [N-Desmethyl]PK11195 by alkylation with [llC]methyl iodide reacting at room temperature in an high-performance liquid chromatography loop, purified and reformulated by solid phase extraction. Synthesis process is carried out in about 35 minutes, and quality control tests were performed to ensure the good quality of product. The specific activity of (R)-[N-MethyJ-11C]PK11195 was 25±10 GBq/μmol, and radiochemical purity was better than 95%.