⁶⁸Ga-PSMA-617: from gallium production by cyclotron to clinical application

Introduction: Prostate cancer (PCa) is the most common cancer in North American men [1]. Patients presenting with metastases or refractory to loco-regional therapy receive androgen deprivation therapy, but it will lead to castration-resistant prostate cancer (CRPC) [2]. Prostate Specific Membrane Antigen (PSMA) ligands, mainly ⁶⁸Ga-PSMA, are used for diagnosis of CRPC. Given the epidemiology of PCa, a widely available radiotracer is needed, but constrained by ⁶⁸Ge/⁶⁸Ga generators’ yield over time. Our project aims to use ⁶⁸Ga produced by cyclotron instead, to allow a larger number of patient’s imaging per synthesis. Here is an overview of this project, from a new technique to improve⁶⁸Ga cyclotron production capacity, to clinical applications.

Methods: We developed a new method to produce ⁶⁸Ga by irradiation of a ⁶⁸Zn-pressed target, and purification by automated module [3]. Cyclotron-produced ⁶⁸Ga-PSMA-617 was characterized in vitro and in vivo. Cell affinity, uptake, internalization and efflux was obtained at 15, 30, 45, 60 and 120 min on LNCaP cells. Distribution patterns of the cyclotron- and generator-produced ⁶⁸Ga-PSMA-617 were compared in healthy mice and dosimetry extrapolation to humans was computed using OLINDA/EXM (Vanderbilt University, 2003). µPET imaging was acquired 60 min following injection of 0,5 MBq of ⁶⁸Ga-PSMA-617 in LNCaP tumor xenograft-bearing athymic nude mice. The results were compared to those of the literature. The clinical part consists on an observational study, part of a larger study in which patients with metastatic CRPC (mCRPC) will be recruited at 5 different sites across Québec.

Results: Irradiation of the ⁶⁸Zn-pressed target, in an in-house designed aluminium magnetic target carrier and automated target dissolution unit, permitted the production of up to 145 GBq of ⁶⁸Ga following 90 min irradiation, with an overall recovery yield of ⁶⁸GaCl₃ of 89% and apparent molar activity of 28.3 ± 6.8 GBq/μmol. Synthesis of cyclotron-produced ⁶⁸Ga-PSMA-617 and quality control were completed in 1h, and the radiopharmaceutical met all specifications. 19 ± 2 GBq of ⁶⁸Ga-PSMA-617 was produced with an estimated production yield of 65-70%. The product was stable for at least 5 h after formulation. The cyclotron- and generator-produced ⁶⁸Ga-PSMA-617 were shown to be radioisotopically, chemically and biologically equivalent. Chemical yield was >95%. In house produced⁶⁸Ga-PSMA-617 showed similar affinity (2.1 nM), uptake and internalization (respectively 11.4 ± 2.1 and 4.4 ± 2.1 % of injected activity/10⁶ cells at 60 min) compared to literature. Comparable biodistribution and imaging patterns were found. Absorbed doses were slightly different than those reported for a similar tracer but stayed in an acceptable range. Health Canada approved the clinical study: at the time of SNMMI meeting, the first results of cyclotron-produced ⁶⁸Ga-PSMA-617 PET/CT will be available and presented.

Conclusions: Thanks to an optimized cyclotron production process, a high activity of ⁶⁸Ga can be produced. It will allow PSMA PET diagnostic imaging for a larger number of patients per synthesis, and higher activity per patient for later imaging acquisition. ⁶⁸Ga-PSMA-617 produced with it in our center has the same in vitro and in vivo characteristics than those of the literature, and acceptable dosimetry. First results of clinical study are expected for the meeting.