Preclinical Evaluation and First Patient Application of 99mTc-PSMA-I&S for SPECT Imaging and Radioguided Surgery in Prostate Cancer

Initial studies in patients have demonstrated the suitability of In-111-PSMA-I&T (In-111-DOTAGA-(3-iodo-y)-f-k-Sub(KuE)) (PSMA is prostate specific membrane antigen and I&T is imaging and therapy) for radio guided surgery (RGS) of small metastatic prostate cancer (PCa) soft-tissue lesions. To meet the clinical need for a more cost-effective altemative, the PSMA-I&T-based tracer concept was adapted to Tc-99m-labeling chemistry. Two PSMA-I&T-derived inhibitors with all-L-serine- (MAS(3)) and all-D-serine- (mas(3)) chelating moieties were evaluated in parallel, and a kit procedure for routine Tc-99m labeling was developed. Methods: PSMA affinities (IC50) and internalization kinetics of Tc-99m-MASS-y-nal-k (Sub-KuE) and Tc-99m-mas(3)-y-nal-k(Sub-KuE) (Tc-99m-PSMA-I&S for imaging and surgery) were determined using LNCaP cells and (I-125-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 of Tc-99m-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) and Tc-99m-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 of Tc-99m-MAS(3)-y-nal-k(Sub-KuE) and Tc-99m-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, Tc-99m-PSMA-I&S was selected for further in vivo evaluation. Compared with In-111-PSMA-I&T, Tc-99m-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 of Tc-99m-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 high Tc-99m-PSMA-I&S uptake in all suspect lesions identified in previous Ga-68-HBED-CC-Ahx-KuE (Ga-68-HBED-CC-PSMA) PET/CT, allowing for their successful intraoperative detection and resection during first-in-human RGS. Conclusion: Because of a straightforward and reliable kit production, Tc-99m-PSMA-I&S represents a cost-effective, readily available alternative to In-111-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 of Tc-99m-PSMA-I&S as a SPECT imaging agent.