Abstract
1200
Introduction: There is a need for better diagnosis and treatment of metastatic prostate cancer (PC), especially when it is castration resistant [1]. Positron emission tomography (PET) using a gallium-68 (68Ga) labeled radiotracer targeting the Prostate Specific Membrane Antigen (PSMA) allows non-invasive imaging of these lesions [2]. However, 68Ga’s half-life is only of 67.7 minutes, which does not allow sufficient time to image the patient after unspecific binding wash-out (e. g. from the bladder). Some radiotracers, such as labeled with lutetium-177 (177Lu), can also target PSMA to deliver endoradiotherapy to the metastases [3]. However, the reactor based 177Lu is not available for local production in Canada. Copper-64 (64Cu), a cyclotron-produced positron (β+), electron (β-) and Auger electron emitter with a half-life of 12.7 hours could be an accessible theranostic solution [4]. We developed DOTHA2, a chelator that allows a stronger binding of 64Cu than its DOTA counterpart [5]. This stronger chelation could result in a more specific distribution of the compound, resulting in an image with better contrast of lesions and a more efficient treatment with lower side effect from non-specific interactions. The objectives of our preclinical study are to evaluate 1) the imaging and 2) the therapeutic potentials of 64Cu-DOTHA2-PSMA (A) in PC animal model.
Methods: Firstly, the 64Cu-DOTHA2-PSMA in vitro behavior (specificity, uptake, internalisation, efflux) was evaluated using human prostate adenocarcinoma cells (LNCaP). Biodistribution was assessed on 30 balb/c mice without tumor (6 mice/time-point from 1h to 24h). Dosimetry was calculated and extrapolated to human using OLINDA/EXM with the balb/c biodistribution results. A 1h dynamic μPET and 4h and 24h post-injection static μPET were performed with LNCAP tumor-bearing NRG mice (n=8, with 3 PMPA blocked scans). These mice were dissected for biodistribution. PET images were compared with 68Ga-DOTA-PSMA. A maximal tolerated dose study (starting dose: 3MBq/g IV [6, 7]) was conducted on NRG mice (daily 21-day follow-up: general well-being and weight). Endoradiotherapy trials were conducted on tumor-bearing NRG mice (n=30) receiving either the optimal dose of 64Cu-DOTHA2-PSMA, its molar equivalent of non-radioactive compound (natCu-DOTHA2-PSMA) as a control or 177Lu-DOTA-PSMA (5 MBq/g IV [8]) (daily 60 days follow : survival and side effects).
Results: 64Cu was cyclotron produced with a 95% yield. Complete complexation to DOTHA2 was achieved in mild conditions in 5 minutes. 64Cu-DOTHA2-PSMA was stable up to 24 hours in solution. At time-points 1h, 2h, 3h and 4h, in vitro studies with n=4 demonstrated high uptake (12.2±2.0%, 27.1±9.1%, 28.8±11.9% and 34.1±19.3%) and internalisation (1.6±0.7%, 14.2±6.0%, 16.5±6.5% and 17.0±7.7%) of 64Cu-DOTHA2-PSMA. Preliminary results showed an advantageous biodistribution with an especially low kidney uptake (17.6±8.0% at 1h to 9.1±1.2% at 2h). The maximal tolerated dose is at least of 5 MBq/g IV (~120MBq/mouse, n=4) and higher doses are on trial at time of abstract submission. A first μPET image (B) shows high contrast of lesions with low captation to the liver. At the SNMMI annual meeting, imaging and radiotherapy results will also be completed and presented.
Conclusions: 64Cu-DOTHA2-PSMA can be synthesized faster and more easily than 64Cu-DOTA-PSMA, while also being more stable. Provisional results predicted 64Cu-DOTHA2-PSMA’s pertinence for imaging and therapy. This radiotracer permits the use of an isotope with a longer half-life than 68Ga for potentially better PET imaging while also being available in Canada for therapy, in opposition to 177Lu. This could offer better PC metastasis diagnosis and treatment for patients. With this preclinical study, we aim to confirm ability to produce images of PC metastases. We also aim to provide evidence, in a pre-clinical model, of the therapeutic potential of 64Cu-DOTHA2-PSMA.