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PET imaging has gained significant momentum in the last few years, especially in the area of oncology, with an increasing focus on metal radioisotopes owing to their versatile chemistry and favourable physical properties. Copper-61 (t1/2 = 3.33 h, 61% β+, Emax = 1.216 MeV) provides unique advantages versus the current clinical standard (i.e., gallium-68) even though, until now, no clinical amounts of 61Cu-based radiopharmaceuticals, other than thiosemicarbazone-based molecules, have been produced. This study aimed to establish a routine production, using a standard medical cyclotron, for a series of widely used somatostatin analogues, currently labelled with gallium-68, that could benefit from the improved characteristics of copper-61. We describe two possible routes to produce the radiopharmaceutical precursor, either from natural zinc or enriched zinc-64 liquid targets and further synthesis of [61Cu]Cu-DOTA-NOC, [61Cu]Cu-DOTA-TOC and [61Cu]Cu-DOTA-TATE with a fully automated GMP-compliant process. The production from enriched targets leads to twice the amount of activity (3.28 ± 0.41 GBq vs. 1.84 ± 0.24 GBq at EOB) and higher radionuclidic purity (99.97% vs. 98.49% at EOB). Our results demonstrate, for the first time, that clinical doses of 61Cu-based radiopharmaceuticals can easily be obtained in centres with a typical biomedical cyclotron optimised to produce 18F-based radiopharmaceuticals.

Background Targeted radionuclide therapy with 177 Lu-labelled small conjugates is expanding rapidly, and its success is linked to appropriate patient selection. Companion diagnostic conjugates are usually labelled with 68 Ga, offering good imaging up to ≈2 h post-injection. However, the optimal tumor-to-background ratio is often reached later. This study examined promising positron-emitting radiometals with half-lives between 3 h and 24 h and β + intensity (I β+ ) ≥ 15% and compared them to 68 Ga. The radiometals included: 43 Sc, 44 Sc, 45 Ti, 55 Co, 61 Cu, 64 Cu, 66 Ga, 85m Y, 86 Y, 90 Nb, 132 La, 150 Tb and 152 Tb. 133 La (7.2% I β+ ) was also examined because it was recently discussed, in combination with 132 La, as a possible diagnostic match for 225 Ac. Methods Total electron and photon doses per decay and per positron; possibly interfering γ-ray emissions; typical activities to be injected for same-day imaging; positron range; and available production routes were examined. Results For each annihilation process useful for PET imaging, the total energy released (MeV) is: 45 Ti (1.5), 43 Sc (1.6), 61 Cu and 64 Cu (1.8), 68 Ga (1.9), 44 Sc and 133 La (2.9), 55 Co (3.2), 85m Y (3.3), 132 La (4.8), 152 Tb (6.5), 150 Tb (7.1), 90 Nb (8.6), and 86 Y (13.6). Significant amounts (≥ 10%) of ≈0.5 MeV photons that may fall into the acceptance window of PET scanners are emitted by 55 Co, 66 Ga, 85m Y, 86 Y, 132 La, and 152 Tb. Compton background from more energetic photons would be expected for 44 Sc, 55 Co, 66 Ga, 86 Y, 90 Nb, 132 La, 150 Tb, and 152 Tb. The mean positron ranges (mm) of 64 Cu (0.6), 85m Y (1.0), 45 Ti (1.5), 133 La (1.6), 43 Sc and 61 Cu (1.7), 55 Co (2.1), 44 Sc and 86 Y (2.5), and 90 Nb (2.6) were lower than that of 68 Ga (3.6). DOTA chelation is applicable for most of the radiometals, though not ideal for 61 Cu/ 64 Cu. Recent data showed that chelation of 45 Ti with DOTA is feasible. 90 Nb requires different complexing agents (e.g., DFO). Finally, they could be economically produced by proton-induced reactions at medical cyclotrons. Conclusion In particular, 43 Sc, 45 Ti, and 61 Cu have overall excellent β + decay-characteristics for theranostic applications complementing 177 Lu-labelled small conjugates, and they could be sustainably produced. Like Lu, 43 Sc, 45 Ti and to a lesser extent 61 Cu could be labelled with DOTA.

Background Fibroblast activation protein (FAP)-targeting radioligands have gained attention for the ability to image multiple tumor types. Current FAP-targeting radioligands are labeled with 68 Ga and 18 F, but their short half-lives limit distribution range after production and later time-point imaging. This study describes the development Kalios, a novel class of NODAGA-conjugated FAP-targeting radioligands labeled with the cyclotron-produced Copper-61 (t 1/2  = 3.33 h), for greater temporal range for FAP-targeted imaging. Results Four Kalios ligands were synthesized and radiolabeled with [ 61 Cu]CuCl 2 in high yield and radiochemical purity within 5 min at room temperature. All radioligands demonstrated high hydrophilicity and strong affinity for FAP, and were primarily internalized after incubation with FAP-positive cells. PET/CT images obtained at 0–1 h and 4 h post-injection (p.i.) illustrated accumulation of all radioligands in FAP-positive tumors. Biodistribution studies of [ 61 Cu]Cu-Kalios-02 demonstrated stable tumor uptake between 1 and 4 h p.i., with washout from normal tissues at 4 h, resulting in improved tumor-to-background ratios. Conclusions Kalios ligands represent a new class of FAP-targeting 61 Cu-labeled radioligands. The half-life of 61 Cu allowed delayed 4-h imaging with improved tumor-to-background ratios. The improved delayed imaging and greater distribution range of these 61 Cu-labeled FAP-targeting radioligands demonstrates their clear potential for clinical translation, while combination with the therapeutic twin 67 Cu allows for truly paired Kalios theranostics.

Background A need for improved, cassette-based automation of 61 Cu separation from irradiated Ni targets was identified given the growing interest in theranostics, and generally lengthy separation chemistries for 64 Cu/ 64 Ni, upon which 61 Cu chemistry is often based. Methods A method for separating 61 Cu from irradiated nat Ni targets was therefore developed, with provision for target recycling. Following deuteron irradiation, electroplated nat Ni targets were remotely transferred from the cyclotron and dissolved in acid. The dissolved target solution was then transferred to an automated FASTlab chemistry module, where sequential TBP and TK201 (Triskem) resins isolated the [ 61 Cu]CuCl 2 , removed Ni, Co, and Fe, and concentrated the product into a formulation suitable for anticipated radiolabelling reactions. Results 61 Cu saturation yields of 190 ± 33 MBq/μA from energetically thick nat Ni targets were measured. The average, decay-corrected, activity-based dissolution efficiency was 97.5 ± 1.4% with an average radiochemical yield of 90.4 ± 3.2% ( N  = 5). The isolated activity was collected approximately 65 min post end of bombardment in ~ 2 mL of 0.06 M HCl (HCl concentration was verified by titration). Quality control of the isolated [ 61 Cu]CuCl 2 ( N  = 5) measured 58 Co content of (8.3 ± 0.6) × 10 − 5 % vs. 61 Cu by activity, Ni separation factors ≥ (2.2 ± 1.8) × 10 6 , EoB molar activities 85 ± 23 GBq/μmol and NOTA-based EoB apparent molar activities of 31 ± 8 MBq/nmol and 201 MBq/nmol for the 30 min and 3.3 h ( N  = 1) irradiations, respectively. Conclusion High purity 61 Cu was produced with the developed automated method using a single-use, cassette-based approach. It was also applicable for 64 Cu, as demonstrated with a single proof-of-concept 64 Ni target production run.

Background A need for improved, cassette-based automation of 61 Cu separation from irradiated Ni targets was identified given the growing interest in theranostics, and generally lengthy separation chemistries for 64 Cu/ 64 Ni, upon which 61 Cu chemistry is often based. Methods A method for separating 61 Cu from irradiated nat Ni targets was therefore developed, with provision for target recycling. Following deuteron irradiation, electroplated nat Ni targets were remotely transferred from the cyclotron and dissolved in acid. The dissolved target solution was then transferred to an automated FASTlab chemistry module, where sequential TBP and TK201 (Triskem) resins isolated the [ 61 Cu]CuCl 2 , removed Ni, Co, and Fe, and concentrated the product into a formulation suitable for anticipated radiolabelling reactions. Results 61 Cu saturation yields of 190 ± 33 MBq/μA from energetically thick nat Ni targets were measured. The average, decay-corrected, activity-based dissolution efficiency was 97.5 ± 1.4% with an average radiochemical yield of 90.4 ± 3.2% ( N  = 5). The isolated activity was collected approximately 65 min post end of bombardment in ~ 2 mL of 0.06 M HCl (HCl concentration was verified by titration). Quality control of the isolated [ 61 Cu]CuCl 2 ( N  = 5) measured 58 Co content of (8.3 ± 0.6) × 10 − 5 % vs. 61 Cu by activity, Ni separation factors ≥ (2.2 ± 1.8) × 10 6 , EoB molar activities 85 ± 23 GBq/μmol and NOTA-based EoB apparent molar activities of 31 ± 8 MBq/nmol and 201 MBq/nmol for the 30 min and 3.3 h ( N  = 1) irradiations, respectively. Conclusion High purity 61 Cu was produced with the developed automated method using a single-use, cassette-based approach. It was also applicable for 64 Cu, as demonstrated with a single proof-of-concept 64 Ni target production run.

[61Cu]diacetyl-bis(N4-methylthiosemicarbazone) ([61Cu] ATSM) was prepared using in house-made diacetyl-bis(N4-methylthiosemicarbazone) (ATSM) ligand and [61Cu]CuCl2 produced via the natZn(p, x)61Cu (180 μA proton irradiation, 22 MeV, 3.2 h) and purified by a ion chromatography method. [61Cu]ATSM radiochemical purity was >98 %, as shown by HPLC and RTLC methods. [61Cu]ATSM was administered into normal and tumor bearing rodents for up to 210 minutes, followed by biodistribution and co-incidence imaging studies. Significant tumor/non-tumor accumulation was observed either by animal sacrification or imaging. [61Cu]ATSM is a positron emission tomography (PET) radiotracer for tumor hypoxia imaging. [61Cu]diacetil-bis(N4-metiltiosemikarbazon) ([61Cu]ATSM) dobiven je iz liganda diacetil-bis(N4-metiltiosemikarbazona) (ATSM) pripravljenog u vlastitom laboratoriju i [61Cu]CuCl2 dobivenog iz natZn(p, x)61Cu (180 μA protonskim zračenjem, 22 MeV, 3,2 h). [61Cu]ATSM je čišćen ionskom kromatografijom. Prema HPLC i RTLC radiokemijska čistoć a bila je > 98 %. [61Cu]ATSM je davan zdravim glodavcima i glodavcima s tumorom tijekom 210 minuta te je praćena biodistribucija. Žrtvovanjem testiranih životinja te snimanjem primijećena je značajna razlika u akumulaciji [61Cu]ATSM u tumorskom tkivu u odnosu na zdravo tkivo. [61Cu]ATSM je pogodan za dijagnostiku hipoksije tumora pozitron emisijskom tomografijom (PET).

[61Cu]diacetil-bis(N4-metiltiosemikarbazon) ([61Cu]ATSM) dobiven je iz liganda diacetil-bis(N4-metiltiosemikarbazona) (ATSM) pripravljenog u vlastitom laboratoriju i [61Cu]CuCl2 dobivenog iz natZn(p,x)61Cu (180 μA protonskim zračenjem, 22 MeV, 3.2 h). [61Cu]ATSM je čišćen ionskom kromatografijom. Prema HPLC i RTLC radiokemijska čistoća bila je > 98%. [61Cu]ATSM je davan zdravim glodavcima i glodavcima s tumorom tijekom 210 minuta te je praćena biodistribucija. Žrtvovanjem testiranih životinja te snimanjem primijećena je značajna razlika u akumulaciji [61Cu]ATSM u tumorskom tkivu u odnosu na zdravo tkivo. [61Cu]ATSM je pogodan za dijagnostiku hipoksije tumora pozitron emisijskom tomografijom (PET).