Synthesis and Biologic Evaluation of Novel 18F-Labeled Probes Targeting Prostate-Specific Membrane Antigen for PET of Prostate Cancer

J Nucl Med. 2016 Dec;57(12):1978-1984. doi: 10.2967/jnumed.116.175810. Epub 2016 Jul 14.

Abstract

Prostate-specific membrane antigen (PSMA) is a membrane protein highly expressed on prostate cancer cells and a potential imaging target for diagnosis. 18F-DCFPyL has been recently developed as an effective probe with high diagnostic accuracy for prostate cancer imaging. However, its radiochemical yield is low. We developed new PSMA probes using succinimidyl 4-18F-fluorobenzoate (18F-SFB), a rapid and effective 18F-labeling agent, taking advantage of the high radiochemical yield of this compound. We evaluated the probes as PET probes for PSMA imaging.

Methods: Four 18F-labeled probes, 18F-8a, 18F-8b, 18F-10a, and 18F-10b, were synthesized using 18F-SFB, and their affinity for PSMA and partition coefficients (log D) were evaluated in vitro. Biodistribution studies were performed in human prostate cancer xenograft-bearing mice. PET images were obtained using 2 compounds, 18F-8a and 18F-10a, and a toxicologic study of 18F-10a was performed.

Results: Four 18F-labeled asymmetric urea compounds, conjugated with 18F-SFB, were synthesized at a radiochemical yield of 30%-50% (decay-corrected), with a radiochemical purity greater than 95%. The radiochemical yield was 10-15 times higher than that of 18F-DCFPyL, the probe currently used in clinical studies. All 4 compounds showed high affinity for PSMA. 18F-8a and 18F-10a had a particularly high binding affinity (Ki values of 3.35 and 2.23 nM, respectively). In the biodistribution study, the accumulation of 18F-8a (13.3 ± 2.2 percentage injected dose per gram [%ID/g]) and 18F-10a (14.0 ± 3.1 %ID/g) in PSMA-positive human prostate (LNCaP) tumors was higher than that of the other 2 compounds and similar to that of 18F-DCFPyL (16.0 ± 2.9 %ID/g). 18F-10a showed the lowest hepatic and intestinal accumulation among the 4 compounds and slightly slower blood clearance than others. In the PET imaging studies, 18F-8a and 18F-10a were clearly visualized in LNCaP in xenograft-bearing mice. 18F-10a showed higher LNCaP-to-liver ratios than 18F-8a. We confirmed the safety profiles of 18F-10a; the no-observed-adverse-effects level was larger than 13.2 μg/kg.

Conclusion: A novel 18F-labeled asymmetric urea compound, 18F-10a, had a high radiochemical yield, high binding affinity for PSMA, and pharmacokinetic profiles suitable for a PSMA imaging probe. We believe that 18F-10a can be effectively and safely used in this type of imaging.

Keywords: 18F-SFB; 18F-labeled asymmetric urea compound; PET; PSMA; prostate cancer.

MeSH terms

  • Animals
  • Antigens, Surface / metabolism*
  • Benzoates / chemical synthesis*
  • Benzoates / chemistry
  • Benzoates / metabolism*
  • Benzoates / pharmacokinetics
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic
  • Chemistry Techniques, Synthetic
  • Glutamate Carboxypeptidase II / metabolism*
  • Humans
  • Male
  • Mice
  • Molecular Probes / chemical synthesis
  • Molecular Probes / chemistry
  • Molecular Probes / metabolism
  • Molecular Probes / pharmacokinetics
  • Organophosphorus Compounds / pharmacology
  • Positron-Emission Tomography / methods*
  • Prostatic Neoplasms / diagnostic imaging*
  • Prostatic Neoplasms / metabolism*
  • Prostatic Neoplasms / pathology
  • Protein Binding / drug effects
  • Radiochemistry
  • Tissue Distribution

Substances

  • 2-(phosphonomethyl)pentanedioic acid
  • Antigens, Surface
  • Benzoates
  • Molecular Probes
  • Organophosphorus Compounds
  • FOLH1 protein, human
  • Glutamate Carboxypeptidase II
  • 4-fluorobenzoic acid