Abstract
PurposeWe present here a Zr-89-labeled inhibitor of prostate-specific membrane antigen (PSMA) as a complement to the already established F-18- or Ga-68-ligands.ProceduresThe precursor PSMA-DFO (ABX) was used for Zr-89-labeling. This is not an antibody, but a peptide analogue of the precursor for the production of [177Lu]Lu-PSMA-617. The ligand [89Zr]Zr-PSMA-DFO was compared with [68Ga]Ga-PSMA-11 and [18F]F-JK-PSMA-7 in vitro by determination of the Kd value, cellular uptake, internalization in LNCaP cells, biodistribution studies with LNCaP prostate tumor xenografts in mice, and in vivo by small-animal PET imaging in LNCaP tumor mouse models. A first-in-human PET was performed with [89Zr]Zr-PSMA-DFO on a patient presenting with a biochemical recurrence after brachytherapy and an ambiguous intraprostatic finding with [18F]F-JK-PSMA-7 but histologically benign cells in a prostate biopsy 7 months previously.Results[89Zr]Zr-PSMA-DFO was prepared with a radiochemical purity ≥ 99.9% and a very high in vitro stability for up to 7 days at 37 °C. All radiotracers showed similar specific cellular binding and internalization, in vitro and comparable tumor uptake in biodistribution experiments during the first 5 h. The [89Zr]Zr-PSMA-DFO achieved significantly higher tumor/background ratios in LNCaP tumor xenografts (tumor/blood: 309 ± 89, tumor/muscle: 450 ± 38) after 24 h than [68Ga]Ga-PSMA-11 (tumor/blood: 112 ± 57, tumor/muscle: 58 ± 36) or [18F]F-JK-PSMA-7 (tumor/blood: 175 ± 30, tumor/muscle: 114 ± 14) after 4 h (p < 0.01). Small-animal PET imaging demonstrated in vivo that tumor visualization with [89Zr]Zr-PSMA-DFO is comparable to [68Ga]Ga-PSMA-11 or [18F]F-JK-PSMA-7 at early time points (1 h p.i.) and that PET scans up to 48 h p.i. clearly visualized the tumor at late time points. A late [89Zr]Zr-PSMA-DFO PET scan on a patient with biochemical recurrence (BCR) had demonstrated intensive tracer accumulation in the right (SUVmax 13.25, 48 h p.i.) and in the left prostate lobe (SUV max 9.47), a repeat biopsy revealed cancer cells on both sides.Conclusion[89Zr]Zr-PSMA-DFO is a promising PSMA PET tracer for detection of tumor areas with lower PSMA expression and thus warrants further clinical evaluation.
Highlights
In current clinical practice, tumor localization in patients with biochemical recurrence (BCR) of prostate cancer is the most accepted and validated field of application of positron emission tomography (PET)/CT with Ga-68 or F-18- prostate-specific membrane antigen (PSMA) ligands [1,2,3]
The stability in PBS was measured in parallel with HPLC at same time intervals, and one single peak was identified at the retention time of [89Zr]Zr-PSMA-DFO (Rt = 9.35 min)
The data collected are not yet sufficient to make generalizable statements about radiation exposure from the radiotracer. This is the subject of a study involving several BCR patients that will be published soon. This preclinical study demonstrates that the tumor uptake and biodistribution of [89Zr]Zr-PSMA-DFO in normal tissues is comparable to that of [68Ga]Ga-PSMA-11 and [18F]F-JKPSMA-7 in the first 5 h
Summary
Tumor localization in patients with biochemical recurrence (BCR) of prostate cancer is the most accepted and validated field of application of PET/CT with Ga-68 or F-18- prostate-specific membrane antigen (PSMA) ligands [1,2,3]. It cannot be ruled out that weakly PSMA-expressing prostate carcinoma foci are overlooked when using short-lived radionuclides for a PET scan [12]. A negative finding after PSMA PET/CT examinations using Ga-68- or F-18-ligands represents a selection of prostate carcinoma foci with absent or weak PSMA expression. The intention of this study was not to develop an alternative to short-lived radiotracers, but to expand the range of available PET tracers if, despite rising prostate-specific antigen (PSA) values, no convincing tumor detection with Ga-68 or F-18 PSMA tracers is possible. We designed [89Zr]Zr-PSMA-DFO for the rare constellation of a BCR, a preceding PSMA-negative scan with Ga-68- or F-18PSMA ligands, and the preference for metastasis-directed therapy over androgen deprivation therapy
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