The work described in this Ph.D. thesis was carried out in the framework of the LARAMED (LAboratory of RAdioisotopes for MEDicine) project at the Legnaro National Laboratories of the National Institute of Nuclear Physics (INFN-LNL). The LARAMED project is a branch of SPES (Selective Production of Exotic Species) with the purpose to evaluate the cyclotron-based production of emerging radionuclides to produce innovative radiopharmaceuticals. This work reports the main results obtained in the COME (COpper MEasurement) and PASTA (Production with Accelerator of Sc-47 for Theranostic Applications) projects in which I was involved in the three years of my Ph.D.. Since the accurate knowledge of the reaction cross section is the first step in the optimization of radioisotope production, both projects were focused on these measurements, for 67Cu and 47Sc respectively, by using proton beams up to 70 MeV. 67Cu and 47Sc are theranostic radionuclides as they can decay simultaneously by γ- and β- emission. This property allows visualization of a specific biological target by γ imaging that, in turn, can be used for applying selectively targeted β- therapy. Worldwide a real problem to be solved is the lack of 67Cu and 47Sc availability, as underlined by the IAEA CRP (No. F22053) focused on the production of the theranostic radionuclides 67Cu, 186Re and 47Sc. In the COME project the first measurements of the 70Zn(p,x)67Cu, 64Cu, 67Ga, 66Ga, 65Zn, and 69mZn cross sections in the 45-70 MeV energy range were obtained. These results, compared with the well-known 68Zn(p,x)67,64Cu nuclear reaction, allowed us to find an optimal energy range to maximize the 67Cu production and, in the same time, minimize the co-produced 64Cu; this result is described in the International Patent n° WO 2019/220224 A1 (November 2019). In the PASTA project the proton-induced reactions on 48Ti and natV targets were investigated. The cross sections values obtained for the 48Ti(p,x)47Sc, 46Sc, 44Sc, 44mSc nuclear reactions show a regular trend, in agreement with the previous experimental data. The results of the natV(p,x)47Sc, 46Sc, 44Sc, 44mSc, 43Sc, 48Sc, 48Cr, 49Cr, 51Cr, 48V, 42K, 43K cross sections were also obtained and compared with literature data and theoretical calculations. Calculations of the Thick Target Yield were also performed for both 67Cu and 47Sc to study the feasibility of their real production by exploiting the nuclear reactions investigated and the 70 MeV proton cyclotron installed at INFN-LNL. For the 47Sc case, dosimetric calculations were performed considering the DOTA-folate conjugate cm10 ([47Sc]-cm10) radiopharmaceutical; the effective Dose Increase (DI) due to the presence of a small amount of the co-produced contaminant 46Sc for Ep<35 MeV was maintained within the 10%, limit required for the radiopharmaceutical clinical use.

Il lavoro descritto in questa tesi di dottorato è stato sviluppato nell’ambito del progetto LARAMED (LAboratory of RAdioisotopes for MEDicine), una branca del progetto SPES (Selective Production of Exotic Species), presso i Laboratori Nazionali di Legnaro dell’Istituto Nazionale di Fisica Nucleare (INFN-LNL). Il progetto LARAMED si propone di studiare la produzione di radionuclidi per la realizzazione di nuovi radiofarmaci, utilizzando il fascio di protoni generato dal ciclotrone SPES. Questo lavoro riporta i principali risultati ottenuti con i progetti COME (COpper MEasurement) e PASTA (Production with Accelerator of Sc-47 for Theranostic Applications) nei quali ho lavorato durante i tre anni di dottorato. Poiché la conoscenza accurata delle sezioni d’urto è il primo step nell’ottimizzazione della produzione di radioisotopi, entrambi i progetti erano focalizzati su queste misure, rispettivamente per il 67Cu e lo 47Sc, usando fasci di protoni di energia fino a 70 MeV. Il 67Cu e lo 47Sc sono radionuclidi teranostici (entrambi emettitori γ- e β- che possono anche essere accoppiati con isotopi β+), permettendo la selezione dei pazienti che hanno una buona probabilità di rispondere positivamente allo specifico radiofarmaco con imaging SPECT (o PET) prima della terapia. Un reale problema da risolvere è la mancanza di disponibilità di 67Cu e 47Sc, come sottolineato dal CRP IAEA (No. F22053) focalizzato sulla produzione dei radionuclidi teranostici 67Cu, 186Re e 47Sc. Nel progetto COME sono state realizzate le prime misure delle sezioni d’urto 70Zn(p,x)67Cu, 64Cu, 67Ga, 66Ga, 65Zn and 69mZn nel range energetico 45-70 MeV. Questi risultati, confrontati con la ben nota reazione nucleare 68Zn(p,x)67,64Cu, mi ha permesso di trovare un range di energia ottimale per massimizzare la produzione di 67Cu e nello stesso tempo minimizzare la produzione dell’isotopo contaminante 64Cu; questo risultato è descritto nel Patent Internazionale n° WO 2019/220224 A1 (Novembre 2019). Nel progetto PASTA sono state investigate le reazioni nucleari indotte da protoni su bersagli di 48Ti e natV. I risultati delle sezioni d’urto delle reazioni nucleari 48Ti(p,x) 47Sc, 46Sc, 44Sc, 44mSc mostrano un trend regolare in accordo con i dati di letteratura. Sono anche stati ottenuti i risultati delle sezioni d’urto natV(p,x)47Sc, 46Sc, 44Sc, 44mSc, 43Sc, 48Sc, 48Cr, 49Cr, 51Cr, 48V, 42K, 43K che sono state confrontate con i dati di letteratura e con alcune stime teoriche. Sono anche stati realizzati dei calcoli di produzione su bersagli spessi, sia nel caso del 67Cu che dello 47Sc per studiare la fattibilità di una reale produzione sfruttando le reazioni nucleari studiate ed il ciclotrone presente presso i LNL. Nel caso dello 47Sc, sono stati effettuati anche calcoli dosimetrici, considerando il radiofarmaco DOTA-folate conjugate cm10 ([47Sc]-cm10). L’incremento della dose efficace dovuta alla presenza di una piccola contaminazione dovuta alla co-produzione di 46Sc è inferiore al 10%, limite richiesto per uso clinico del radiofarmaco, per Ep<35 MeV.

Cyclotron production of theranostic radionuclides: 67Cu and 47Sc

MOU, LILIANA
2020

Abstract

The work described in this Ph.D. thesis was carried out in the framework of the LARAMED (LAboratory of RAdioisotopes for MEDicine) project at the Legnaro National Laboratories of the National Institute of Nuclear Physics (INFN-LNL). The LARAMED project is a branch of SPES (Selective Production of Exotic Species) with the purpose to evaluate the cyclotron-based production of emerging radionuclides to produce innovative radiopharmaceuticals. This work reports the main results obtained in the COME (COpper MEasurement) and PASTA (Production with Accelerator of Sc-47 for Theranostic Applications) projects in which I was involved in the three years of my Ph.D.. Since the accurate knowledge of the reaction cross section is the first step in the optimization of radioisotope production, both projects were focused on these measurements, for 67Cu and 47Sc respectively, by using proton beams up to 70 MeV. 67Cu and 47Sc are theranostic radionuclides as they can decay simultaneously by γ- and β- emission. This property allows visualization of a specific biological target by γ imaging that, in turn, can be used for applying selectively targeted β- therapy. Worldwide a real problem to be solved is the lack of 67Cu and 47Sc availability, as underlined by the IAEA CRP (No. F22053) focused on the production of the theranostic radionuclides 67Cu, 186Re and 47Sc. In the COME project the first measurements of the 70Zn(p,x)67Cu, 64Cu, 67Ga, 66Ga, 65Zn, and 69mZn cross sections in the 45-70 MeV energy range were obtained. These results, compared with the well-known 68Zn(p,x)67,64Cu nuclear reaction, allowed us to find an optimal energy range to maximize the 67Cu production and, in the same time, minimize the co-produced 64Cu; this result is described in the International Patent n° WO 2019/220224 A1 (November 2019). In the PASTA project the proton-induced reactions on 48Ti and natV targets were investigated. The cross sections values obtained for the 48Ti(p,x)47Sc, 46Sc, 44Sc, 44mSc nuclear reactions show a regular trend, in agreement with the previous experimental data. The results of the natV(p,x)47Sc, 46Sc, 44Sc, 44mSc, 43Sc, 48Sc, 48Cr, 49Cr, 51Cr, 48V, 42K, 43K cross sections were also obtained and compared with literature data and theoretical calculations. Calculations of the Thick Target Yield were also performed for both 67Cu and 47Sc to study the feasibility of their real production by exploiting the nuclear reactions investigated and the 70 MeV proton cyclotron installed at INFN-LNL. For the 47Sc case, dosimetric calculations were performed considering the DOTA-folate conjugate cm10 ([47Sc]-cm10) radiopharmaceutical; the effective Dose Increase (DI) due to the presence of a small amount of the co-produced contaminant 46Sc for Ep<35 MeV was maintained within the 10%, limit required for the radiopharmaceutical clinical use.
DUATTI, Adriano
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11392/2488256
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