In vitro and in vivo comparative study of a novel 68Ga-labeled PSMA-targeted inhibitor and 68Ga-PSMA-11.

68Ga-radiolabeled small molecules that specifically target prostate-specific membrane antigen (PSMA) have been extensively investigated, and some of these tracers have been used in the diagnosis of prostate cancer via 68Ga-positron emission tomography (68Ga-PET). Nevertheless, current 68Ga-labeled radiotracers show only fair detection rates for metastatic prostate cancer lesions, especially those with lower levels of prostate specific antigen (PSA), which often occurs in the biochemical recurrence of prostate cancer. The goal of this study was to design and synthesize a new PSMA-targeted radiotracer, 68Ga-SC691, with high affinity for prostate cancer cells and excellent pharmacokinetics. To this end, structural optimization was carried out on the bifunctional group, target motif, and linker while the high affinity targeting scaffold remained. To explore its potential in the clinic, a comparative study was further performed in vitro and in vivo between 68Ga-SC691 and 68Ga-PSMA-11, a clinically approved tracer for PSMA-positive prostate cancer. SC691 was radiolabeled to provide 68Ga-SC691 in 99% radiolabeling yield under mild conditions. High uptake and a high internalization ratio into LNCaP cells were observed in in vitro studies. In vivo studies showed that 68Ga-SC691 had favorable biodistribution properties and could specifically accumulate on PSMA-positive LNCaP xenografts visualized by micro-PET/CT. This radiotracer showed excellent PET imaging quality and comparable, if not higher, uptake in LNCaP xenografts than 68Ga-PSMA-11.

Early differences in dynamic uptake of 68Ga-PSMA-11 in primary prostate cancer: A test-retest study.

INTRODUCTION: Dynamic PET/CT allows visualization of pharmacokinetics over the time, in contrast to static whole body PET/CT. The objective of this study was to assess 68Ga-PSMA-11 uptake in pathological lesions and benign tissue, within 30 minutes after injection in primary prostate cancer (PCa) patients in test-retest setting. MATERIALS AND METHODS: Five patients, with biopsy proven PCa, were scanned dynamically in list mode for 30 minutes on a digital PET/CT-scanner directly after an intravenous bolus injection of 100 MBq 68Ga-PSMA-11. Approximately 45 minutes after injection a static whole body scan was acquired, followed by a one bed position scan of the pelvic region. The scans were repeated approximately four weeks later, without any intervention in between. Semi-quantitative assessment was performed using regions-of-interest in the prostate tumor, bladder, gluteal muscle and iliac artery. Time-activity curves were extracted from the counts in these regions and the intra-patient variability between both scans was assessed. RESULTS: The uptake of the iliac artery and gluteal muscle reached a plateau after 5 and 3 minutes, respectively. The population fell apart in two groups with respect to tumor uptake: in some patients the tumor uptake reached a plateau after 5 minutes, whereas in other patients the uptake kept increasing, which correlated with larger tumor volumes on PET/CT scan. Median intra-patient variation between both scans was 12.2% for artery, 9.7% for tumor, 32.7% for the bladder and 14.1% for the gluteal muscle. CONCLUSION: Dynamic 68Ga-PSMA-11 PET/CT scans, with a time interval of four weeks, are reproducible with a 10% variation in uptake in the primary prostate tumor. An uptake plateau was reached for the iliac artery and gluteal muscle within 5 minutes post-injection. A larger tumor volume seems to be related to continued tumor uptake. This information might be relevant for both response monitoring and PSMA-based radionuclide therapies.

Can SUVmax of 68Ga-labeled PSMA Ligand and 18F-choline PET/CT Be Used to Predict the Radiation Dose in Prostate Cancer Patients?

Gallium-68 (Ga)-PSMA and F-Choline are two radionuclides that have already shown high potential for the detection of prostate cancer. The comparison between these two radionuclides has several advantages in radiation protection. The aim of this prospective study was to identify which of these two radionuclides can help in predicting the equivalent dose using the maximum standard uptake value (SUVmax) of normal organs, the kidneys. Two groups of 40 patients (total n = 80) who underwent PET/CT using Ga or F for diagnosis of prostate cancer between April 2018 and December 2018 at the American University of Beirut Medical Center were included. First, the dose rates were measured after 1 h of radionuclide uptake at 1 m distance with background of 0.015 µSv h. Then, SUVmax for kidneys were determined from images obtained with PET/CT 1 h after injection of both radionuclides. The ratios of the equivalent doses to the SUVmax for kidneys were compared for both Ga-PSMA and F-Choline. There is a positive moderate relationship between the SUVmax for kidneys and the Ga dose rate after 1 h of injection at 1 m distance from the abdomen (p-value = 0.023 < 0.05). This relationship is statistically significant. However, there is a very low negative relationship between the SUVmax kidney and F dose rate after 1 h of injection at 1 m distance from the abdomen (p-value = 0.93 > 0.05). This relationship is not statistically significant. This leads to the suggestion that we can predict the equivalent dose due to Ga by indicating the SUVmax from the PET/CT images.

Gallium and its competing roles with iron in biological systems.

Gallium, a group IIIa metal, shares chemical properties with iron. Studies have shown that gallium-based compounds have potential therapeutic activity against certain cancers and infectious microorganisms. By functioning as an iron mimetic, gallium perturbs iron-dependent proliferation processes in tumor cells. Gallium's action on iron homeostasis leads to disruption of ribonucleotide reductase, mitochondrial function, and the regulation of transferrin receptor and ferritin. In addition, gallium nitrate stimulates an increase in mitochondrial reactive oxygen species in cells which triggers downstream upregulation of metallothionein and hemoxygenase-1. Gallium's anti-infective activity against bacteria and fungi results from disruption of microbial iron utilization through mechanisms which include gallium binding to siderophores and downregulation of bacterial iron uptake. Gallium compounds lack cross-resistance to conventional chemotherapeutic drugs and antibiotics thus making them attractive agents for drug development. This review will focus on the mechanisms of action of gallium with emphasis on its interaction with iron and iron proteins.

Triaza-based amphiphilic chelators: synthetic route, in vitro characterization and in vivo studies of their Ga(III) and Al(III) chelates.

Radiogallium chelates are important for diagnostic imaging in nuclear medicine (PET (positron emission tomography) and gamma-scintigraphy). Micelles are adequate colloidal vehicles for the delivery of therapeutic and diagnostic agents to organs and tissues. In this paper we describe the synthesis and in vitro and in vivo studies of a series of micelles-forming Ga(III) chelates targeted for the liver. The amphiphilic ligands are based on NOTA (NOTA=1,4,7-triazacyclonoane-N,N'N''-triacetic acid) and bear a alpha-alkyl chain in one of the pendant acetate arms (the size of the chain changes from four to fourteen carbon atoms). A multinuclear NMR study ((1)H, (13)C, (27)Al and (71)Ga) gave some insights into the structure and dynamics of the metal chelates in solution, consistent with their rigidity and octahedral or pseudo-octahedral geometry. The critical micellar concentration of the chelates was determined using a fluorescence method and (27)Al NMR spectroscopy (Al(III) was used as a surrogate of Ga(III)), both showing similar results and suggesting that the chelates of NOTAC6 form pre-micellar aggregates. The logP (octanol-water) determination showed enhancement of the lipophilic character of the Ga(III) chelates with the increase of the number of carbons in the alpha-alkyl chain. Biodistribution and gamma-scintigraphic studies of the (67)Ga(III) labeled chelates were performed on Wistar rats, showing higher liver uptake for [(67)Ga](NOTAC8) in comparison to [(67)Ga](NOTAC6), consistent with a longer alpha-alkyl chain and a higher lipophilicity. After 24h both chelates were completely cleared off from the tissues and organs with no deposition in the bones and liver/spleen. [(67)Ga](NOTAC8) showed high kinetic stability in blood serum.