title: Preclinical evaluation of BAY 1075553, a novel (18)F-labelled inhibitor of prostate-specific membrane antigen for PET imaging of prostate cancer.
abstract: OBJECTIVE
  Prostate-specific membrane antigen (PSMA) is a transmembrane protein overexpressed in prostate cancer and is therefore being explored as a biomarker for diagnosing and staging of the disease. Here we report preclinical data on BAY 1075553 (a 9:1 mixture of (2S,4S)- and (2R,4S)-2-[(18)F]fluoro-4-phosphonomethyl-pentanedioic acid), a novel (18)F-labelled small molecule inhibitor of PSMA enzymatic activity, which can be efficiently synthesized from a direct radiolabelling precursor.
  
  
  METHODS
  The (18)F-radiolabelled stereoisomers of 2-[(18)F]fluoro-4-(phosphonomethyl)-pentanedioic acid were synthesized from their respective isomerically pure precursors dimethyl 2-{[bis(benzyloxy)phosphoryl]methyl}-4-(tosyloxy)pentanedioate. In vivo positron emission tomography (PET) imaging and biodistribution studies were conducted in mice bearing LNCaP, 22Rv1 and PC-3 tumours. Pharmacokinetic parameters and dosimetry estimates were calculated based on biodistribution studies in rodents. For non-clinical safety assessment (safety pharmacology, toxicology) to support a single-dose human microdose study, off-target effects in vitro, effects on vital organ functions (cardiovascular in dogs, nervous system in rats), mutagenicity screens and an extended single-dose study in rats were conducted with the non-radioactive racemic analogue of BAY 1075553.
  
  
  RESULTS
  BAY 1075553 showed high tumour accumulation specific to PSMA-positive tumour-bearing mice and was superior to other stereoisomers tested. Fast clearance of BAY 1075553 resulted overall in low background signals in other organs except for high uptake into kidney and bladder which was mainly caused by renal elimination of BAY 1075553. A modest uptake into bone was observed which decreased over time indicating organ-specific uptake as opposed to defluorination of BAY 1075553 in vivo. Biodistribution studies found highest organ doses for kidneys and the urinary bladder wall resulting in a projected effective dose (ED) in humans of 0.0219 mSv/MBq. Non-clinical safety studies did not show off-target activity, effects on vital organs function or dose-dependent adverse effects.
  
  
  CONCLUSIONS
  BAY 1075553 was identified as a promising PET tracer for PSMA-positive prostate tumours in preclinical studies. BAY 1075553 can be produced using a robust, direct radiosynthesis procedure. Pharmacokinetic, toxicology and safety pharmacology studies support the application of BAY 1075553 in a first-in-man microdose study with single i.v. administration.
authors: Global Drug Discovery, Bayer Healthcare, Berlin, Germany, Muellerstrasse 178, 13342, Berlin, Germany, ralf.lesche@bayer.com.
authors: Ralf
authors: R
authors: Lesche
authors: Georg
authors: G
authors: Kettschau
authors: Alexey V
authors: AV
authors: Gromov
authors: Niels
authors: N
authors: Böhnke
authors: Sandra
authors: S
authors: Borkowski
authors: Ursula
authors: U
authors: Mönning
authors: Christa
authors: C
authors: Hegele-Hartung
authors: Olaf
authors: O
authors: Döhr
authors: Ludger M
authors: LM
authors: Dinkelborg
authors: Keith
authors: K
authors: Graham
mesh_terms: D000818:Animals; D000954:Antigens, Surface; D004285:Dogs; D005260:Female; D005462:Fluorine Radioisotopes; D043425:Glutamate Carboxypeptidase II / Q000037:antagonists & inhibitors*; D005977:Glutarates / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D007553:Isotope Labeling; D008297:Male; D051379:Mice; D063065:Organophosphonates / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D049268:Positron-Emission Tomography / Q000379:methods*; D011471:Prostatic Neoplasms / Q000000981:diagnostic imaging*; D011849:Radioactive Tracers; D011854:Radiochemistry; D019275:Radiopharmaceuticals / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D012449:Safety; D013237:Stereoisomerism
chemical_list: C000589485:2-fluoro-4-phosphonomethylpentanedioic acid; D000954:Antigens, Surface; D005462:Fluorine Radioisotopes; D005977:Glutarates; D063065:Organophosphonates; D011849:Radioactive Tracers; D019275:Radiopharmaceuticals; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II
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