64Cu-DOTHA2-PSMA, a Novel PSMA PET Radiotracer for Prostate Cancer with a Long Imaging Time Window

Abstract

Prostate cancer imaging and late-stage management can be improved with prostate-specific membrane antigen (PSMA)-targeting radiotracers. We developed a PSMA positron emission tomography (PET) radiotracer, DOTHA2-PSMA radiolabeled with 64Cu (T1/2: 12.7 h), to leverage its large imaging time window. This preclinical study aimed to evaluate the biological and imaging properties of 64Cu-DOTHA2-PSMA. Its stability was assessed in plasma ex vivo and in mice. Cellular behavior was studied for up to 48 h in LNCaP cells. Biodistribution studies were performed in balb/c mice for up to 48 h. Dynamic (1 h) and static (4 h and 24 h) PET imaging was completed in LNCaP tumor-bearing mice. 64Cu-DOTHA2-PSMA was stable ex vivo in plasma and reached cellular internalization up to 34.1 ± 4.9% injected activity (IA)/106 cells at 48 h post-injection (p.i.). Biodistribution results showed significantly lower uptake in kidneys than 68Ga-PSMA-617, our reference PET tracer (p < 0.001), but higher liver uptake at 2 h p.i. (p < 0.001). PET images showed 64Cu-DOTHA2-PSMA’s highest tumoral uptake at 4 h p.i., with a significant difference between blocked and non-blocked groups from the time of injection to 24 h p.i. The high stability and tumor uptake with a long tumor imaging time window of 64Cu-DOTHA2-PSMA potentially contribute to the prostate cancer theranostic approach and its local recurrence detection.

Theranostic 64Cu-DOTHA2-PSMA allows low toxicity radioligand therapy in mice prostate cancer model

“…64 Cu-DOTHA 2 -PSMA was synthesized, radiolabeled and characterized as previously described with a 116 ± 30 MBq/nmol molar activity ( 31 ).…”

“…For survival assays, human prostate adenocarcinoma LNCaP cells (ATCC) xenografts were implanted 4 ± 1 weeks before the experiment by injecting 200 µL of a 1:1 matrigel (Fisher Scientific)/phoshate-buffered saline (Wisent) mixture containing 8 × 10 6 LNCaP cells subcutaneously on mice shoulders. LNCaP PSMA expression was previously verified ( 31 ). Protocols were approved by the Animal Ethics Committee of the Université de Sherbrooke according to the Canadian Council on Animal Care guidelines.…”

“…In this regard, we developed the radioligand 64 Cu-DOTHA 2 -PSMA ( Figure 1 ) to overcome 64 Cu complexation challenges. Indeed, DOTHA 2 offers fast complexation kinetics and high in vivo stability ( 31 ). It achieved high tumoral uptake up to 24h post-injection (p.i.)…”

“…It achieved high tumoral uptake up to 24h post-injection (p.i.) on preclinical PET imaging ( 31 ). 64 Cu-DOTHA 2 -PSMA shown to be mainly cleared through the hepatobiliary pathway, which could be explained by its lipophilicity (log D = −0.96 ± 0.61) and its binding to plasma proteins; this was accompanied by a low kidney uptake and a fast-urinary clearance pattern ( 31 ).…”

“…on preclinical PET imaging ( 31 ). 64 Cu-DOTHA 2 -PSMA shown to be mainly cleared through the hepatobiliary pathway, which could be explained by its lipophilicity (log D = −0.96 ± 0.61) and its binding to plasma proteins; this was accompanied by a low kidney uptake and a fast-urinary clearance pattern ( 31 ). PSMA-617 radioligands have mainly urinary clearance with higher kidney uptake, especially at early time points ( 9 ).…”