Preparation of ⁶⁸Ga-PSMA-11 with a Synthesis Module for Micro PET-CT Imaging of PSMA Expression during Prostate Cancer Progression

Abstract

Objective To synthesize 68Ga-Glu-urea-Lys(Ahx)-HBED-CC (68Ga-PSMA-11) with a synthesis module and investigate PET-CT imaging to monitor PSMA expression during prostate cancer (PCa) progression and tumor growth in mice bearing subcutaneous PCa xenografts. Method The radiochemical purity and stability of 68Ga-PSMA-11 were determined via radio-HPLC. The PCa cell lines of different PSMA expression levels (PC3, VCAP±, CWR22RV1+, and LNCaP++) were selected to mimic the PCa progression. 68Ga-PSMA-11 biodistribution was studied by dissection method and in vivo imaging with micro PET-CT. The expression levels of PSMA in tumor cells and tissues were analyzed by immunofluorescence, flow cytometry, and western blot. The correlation between PSMA expression and radio-uptake was also evaluated. 2-PMPA preadministration served as a block group. Results The radiochemical purity of 68Ga-PSMA-11 was 99.6 ± 0.1% and stable in vitro for 2 h. The equilibrium binding constant (Kd) of 68Ga-PSMA-11 to LNCaP, CWR22Rv1, PC-3, and VCAP cells was 4.3 ± 0.8 nM, 16.4 ± 1.3 nM, 225.3 ± 20.8 nM, and 125.6 ± 13.1 nM, respectively. Results of tumor uptake (% ID and % ID/g or % ID/cm3) of 68Ga-PSMA-11 in biodistribution and micro PET imaging were LNCaP > CWR22RV1 > PC-3 and VCAP due to different PSMA expression levels. It was confirmed by flow cytometry, western blot, and immunofluorescence. Tumor uptake (% ID/cm3) of 68Ga-PSMA-11 increased with the tumor anatomical volume in quadratic polynomial fashion and reached the peak (when tumor volume was 0.5 cm3) earlier than tumor uptake (% ID). Tumor uptake (% ID/cm3) of 68Ga-PSMA-11 based on functional volume correlated well with the PSMA expression in a linear manner (y = 9.35x + 2.59, R2 = 0.8924, and p < 0.0001); however, low dose 2-PMPA causes rapid renal clearance of increased tumor/kidney uptake of 68Ga-PSMA-11. Conclusions The 68Ga-PSMA-11 PET-CT imaging could invasively evaluate PSMA expression during PCa progression and tumor growth with % ID/cm3 (based on functional volume) as an important index. Low dose 2-PMPA preadministration might be a choice to decrease kidney uptake of 68Ga-PSMA-11.

A comparative study of peptide-based imaging agents [68Ga]Ga-PSMA-11, [68Ga]Ga-AMBA, [68Ga]Ga-NODAGA-RGD and [68Ga]Ga-DOTA-NT-20.3 in preclinical prostate tumour models

“…As expected and already reported using PSMA-based radioligands in PCa models, the tumour uptake of [ 68 Ga]Ga-PSMA-11 was high in 22Rv1 derived tumour and negative in PC3 one, well correlated with PSMA expression [29]. Similarly to Wang et al [29], we found elevated uptake and undesired retention of [ 68 Ga]Ga-PSMA-11 in kidneys, in good agreement with the substantial PSMA expression observed in this organ in mice and in humans [30]. Despite [ 68 Ga]Ga-PSMA-11 PET/CT being currently widely used in patients for the management of all stages of PCa, potential pitfalls therefore still exist in PSMA-based imaging approaches, especially due to the lack of PSMA overexpression in some primary tumours as well as the loss of PSMA expression in poorly differentiated tumour with NED [10,31].…”

“…PSMA has obviously emerged in the past decade as one of the most favourable targets for PET imaging and radionuclide based therapy [28]. As expected and already reported using PSMA-based radioligands in PCa models, the tumour uptake of [ 68 Ga]Ga-PSMA-11 was high in 22Rv1 derived tumour and negative in PC3 one, well correlated with PSMA expression [29]. Similarly to Wang et al [29], we found elevated uptake and undesired retention of [ 68 Ga]Ga-PSMA-11 in kidneys, in good agreement with the substantial PSMA expression observed in this organ in mice and in humans [30].…”

Intra-individual dynamic comparison of 18F-PSMA-11 and 68Ga-PSMA-11 in LNCaP xenograft bearing mice

“…(10.3 ± 2.2 nM in C4-2 cells) 10 and for 68 Ga-PSMA-11 by Wang et al . (4.3 ± 0.8 nM in LNCaP cells) 19 and Sanchez-Crespo et al . (27.05 nM in LNCaP cells) 20 .…”

“…In vitro characterization of 18 19 and Sanchez-Crespo et al (27.05 nM in LNCaP cells) 20 . The recently evaluated 18 F-PSMA-BCH demonstrated a comparable K d value of 2.90 ± 0.83 nM in 22Rv1 cells 21 .…”

Automated radiosynthesis of [68Ga]Ga‐PSMA‐11 and [177Lu]Lu‐PSMA‐617 on the iPHASE MultiSyn module for clinical applications

“…Protocols for the manual, semiautomatic and fully automatic production of [ 68 Ga]Ga‐PSMA‐11 have been published with overall radiochemical production yields for manual and semiautomatic processes generally >90% 17–22 and fully automated procedures including product formulation ranging between 57‐80% decay‐corrected (d.c.) radiochemical yield 23–28 . Manual and fully automated production of [ 177 Lu]Lu‐PSMA‐617 has been reported in >90% radiochemical yields 29–32 …”