The gallium-68 (⁶⁸Ga) generator offers PET molecular imaging to hospitals without a cyclotron if simple labelling methods are devised. Current ⁶⁸Ga clinical radiopharmaceutical syntheses require high temperatures (> 90 °C), extended reaction times (5 – 20 min) and post-synthetic purification (– for example, ⁶⁸Ga-PSMA-HBED-CC for metastatic prostate cancer). We have previously shown that tris(hydroxypyridinone) (THP) ligands rapidly label with ⁶⁸Ga³⁺ quantitatively under mild conditions (Chem Commun, 2011; 47:7068).

We now report the development of a kit-based ⁶⁸Ga radiopharmaceutical for imaging prostate specific membrane antigen (PSMA) expression in metastatic prostate cancer. A novel PSMA-targeted THP peptide bioconjugate, THP-PSMA, has been synthesised. THP-PSMA can be formulated in a sterile kit, suitable for one-step, GMP-compliant clinical preparations of ⁶⁸Ga-THP-PSMA. Addition of generator-produced ⁶⁸Ga to the kit results in >95% radiochemical yield of ⁶⁸Ga-THP-PSMA in < 5 min, at pH 7 and ambient temperature, requiring no post-synthetic purification or formulation.

Preclinical PET/CT and ex vivo biodistribution studies demonstrate that ⁶⁸Ga-THP-PSMA selectively accumulates in PSMA-positive DU145-PSMA tumours (16.7±7.4 %ID g^-1), with minimal uptake in PSMA-negative DU145 tumours (0.7±0.7 %ID g^-1). Specificity has been confirmed by blocking studies (1.4±0.2 %ID g^-1). Biodistribution and tumour uptake have been compared to the clinical standard, ⁶⁸Ga-PSMA-HBED-CC, and show no statistically significant differences except lower spleen uptake for ⁶⁸Ga-THP-PSMA.

A first-in-man clinical trial is being undertaken, with the first PET/CT patient scans indicating that ⁶⁸Ga-THP-PSMA is safe, and that focal uptake in prostate adenocarcinoma correlates with high PSMA expression. Additionally, non-specific uptake in healthy tissue appears lower than the current clinical standard, ⁶⁸Ga-PSMA-HBED-CC.