Initial studies in patients have demonstrated the suitability of (111)In-PSMA-I&T ((111)In-DOTAGA-(3-iodo-y)-f-k-Sub(KuE)) 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 to (99m)Tc-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 routine (99m)Tc-labeling was developed.
PSMA-affinities (IC50) and internalization kinetics of (99m)Tc-MAS3-y-nal-k(Sub-KuE) and (99m)Tc-mas3-y-nal-k(Sub-KuE) ("(99m)Tc-PSMA-I&S" for Imaging and Surgery) were determined using LNCaP cells and ((125)I-BA)KuE as radioligand and reference standard. In vivo metabolite analyses and biodistribution studies were carried out using CD-1 nu/nu and LNCaP-tumor bearing CB-17-SCID mice. Pharmacokinetics of (99m)Tc-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 21h p.i. Additionally, preoperative SPECT/CT (12h p.i.) and (99m)Tc-PSMA-I&S-supported RGS (16h p.i.) were performed in one PCa patient with proven iliac and inguinal lymph node metastases.
A robust and reliable kit-labeling procedure was established, allowing the preparation of (99m)Tc-MAS3-y-nal-k(Sub-KuE) and (99m)Tc-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, (99m)Tc-PSMA-I&S was selected for further in vivo evaluation. Compared to (111)In-PSMA-I&T, (99m)Tc-PSMA-I&S showed delayed clearance kinetics, but identical uptake in PSMA+ tissues in the LNCaP xenograft model (1h p.i.). In exemplary PCa patients, relatively slow whole-body clearance of (99m)Tc-PSMA-I&S was also observed due to high plasma protein binding (94%) of the tracer. This, however, promoted efficient tracer uptake in PCa lesions over time, and lead to steadily increasing lesion-to-background ratios up to 21h p.i.. Preoperative SPECT/CT showed high (99m)Tc-PSMA-I&S uptake in all suspect lesions identified in previous (68)Ga-HBED-CC-PSMA PET/CT, allowing for their successfully intraoperative detection and resection during first-in-man RGS.
Due to a straightforward and reliable kit-production, (99m)Tc-PSMA-I&S represents a cost-effective, readily available alternative to (111)In-PSMA-I&T. Initial patient data indicate its comparable or even superior performance as a probe for PSMA-targeted RGS and also hint towards the unexpected potential of (99m)Tc-PSMA-I&S as a SPECT imaging agent.
Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 2016 Sep 15 [Epub ahead of print]
Stephanie Robu, Margret Schottelius, Matthias Eiber, Tobias Maurer, Jürgen Gschwend, Markus Schwaiger, Hans-Jürgen Wester
Technische Universität München, Germany.