title: Preclinical Evaluation and First Patient Application of 99mTc-PSMA-I&S for SPECT Imaging and Radioguided Surgery in Prostate Cancer.
abstract: Initial studies in patients have demonstrated the suitability of111In-PSMA-I&T (111In-DOTAGA-(3-iodo-y)-f-k-Sub(KuE)) (PSMA is prostate-specific membrane antigen and I&T is imaging and therapy) for radioguided surgery (RGS) of small metastatic prostate cancer (PCa) soft-tissue lesions. To meet the clinical need for a more cost-effective alternative, the PSMA-I&T-based tracer concept was adapted to99mTc-labeling chemistry. Two PSMA-I&T-derived inhibitors with all-L-serine- (MAS3) and all-D-serine- (mas3) chelating moieties were evaluated in parallel, and a kit procedure for routine99mTc labeling was developed.
  
  
  METHODS
  PSMA affinities (IC50) and internalization kinetics of99mTc-MAS3-y-nal-k(Sub-KuE) and99mTc-mas3-y-nal-k(Sub-KuE) (99mTc-PSMA-I&S for imaging and surgery) were determined using LNCaP cells and (125I-BA)KuE as a radioligand and reference standard. In vivo metabolite analyses and biodistribution studies were performed using CD-1 nu/nu and LNCaP tumor-bearing CB-17 severe combined immunodeficiency mice. The pharmacokinetics of99mTc-PSMA-I&S in humans were investigated in a patient with advanced metastatic PCa via sequential planar whole-body SPECT imaging at 1, 3, 5, and 21 h after injection. Additionally, preoperative SPECT/CT (12 h after injection) and99mTc-PSMA-I&S-supported RGS (16 h after injection) were performed in 1 PCa patient with proven iliac and inguinal lymph node metastases.
  
  
  RESULTS
  A robust and reliable kit-labeling procedure was established, allowing the preparation of99mTc-MAS3-y-nal-k(Sub-KuE) and99mTc-PSMA-I&S in consistently high radiochemical yield and purity (≥98%, n > 50 preparations). Because of its improved internalization efficiency and superior in vivo stability,99mTc-PSMA-I&S was selected for further in vivo evaluation. Compared with111In-PSMA-I&T,99mTc-PSMA-I&S showed delayed clearance kinetics but identical uptake in PSMA-positive tissues in the LNCaP xenograft model (1 h after injection). In exemplary PCa patients, a relatively slow whole-body clearance of99mTc-PSMA-I&S was observed due to high plasma protein binding (94%) of the tracer. This, however, promoted efficient tracer uptake in PCa lesions over time and led to steadily increasing lesion-to-background ratios up to 21 h after injection. Preoperative SPECT/CT showed a high99mTc-PSMA-I&S uptake in all suspect lesions identified in previous68Ga-HBED-CC-Ahx-KuE (68Ga-HBED-CC-PSMA) PET/CT, allowing for their successful intraoperative detection and resection during first-in-human RGS.
  
  
  CONCLUSIONS
  Because of a straightforward and reliable kit production,99mTc-PSMA-I&S represents a cost-effective, readily available alternative to111In-PSMA-I&T. Initial patient data indicate its comparable or even superior performance as a probe for PSMA-targeted RGS and also hint toward the unexpected potential of99mTc-PSMA-I&S as a SPECT imaging agent.
authors.affiliation: Chair of Pharmaceutical Radiochemistry, Technische Universität München, Garching, Germany stephanie.robu@tum.de.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Robu
authors.affiliation: Chair of Pharmaceutical Radiochemistry, Technische Universität München, Garching, Germany.
authors.forename: Margret
authors.initials: M
authors.lastname: Schottelius
authors.affiliation: Department of Nuclear Medicine, Klinikum Rechts der Isar, Technische Universität München, München, Germany; and.
authors.forename: Matthias
authors.initials: M
authors.lastname: Eiber
authors.affiliation: Department of Urology, Klinikum Rechts der Isar, Technische Universität München, München, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Maurer
authors.affiliation: Department of Urology, Klinikum Rechts der Isar, Technische Universität München, München, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Gschwend
authors.affiliation: Department of Nuclear Medicine, Klinikum Rechts der Isar, Technische Universität München, München, Germany; and.
authors.forename: Markus
authors.initials: M
authors.lastname: Schwaiger
authors.affiliation: Chair of Pharmaceutical Radiochemistry, Technische Universität München, Garching, Germany.
authors.forename: Hans-Jürgen
authors.initials: HJ
authors.lastname: Wester
mesh_terms: D000368:Aged; D000818:Animals; D000954:Antigens, Surface; D043425:Glutamate Carboxypeptidase II; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D010865:Pilot Projects; D011468:Prostatectomy / Q000379:methods; D011471:Prostatic Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000601:surgery*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D025321:Surgery, Computer-Assisted / Q000379:methods*; D013667:Technetium; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods*; D016896:Treatment Outcome
chemical_list: D000954:Antigens, Surface; D019275:Radiopharmaceuticals; D013667:Technetium; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II
keywords: 111In-PSMA-I&T; 99mTc-PSMA-I&S; PSMA; RGS; SPECT; gamma probe; radioguided surgery