Technetium Tc 99m trofolastat

This case series evaluated the feasibility of prostate-specific membrane antigen (PSMA)-radioguided surgery (RGS) with ^99mTc-MIP-1404 in recurrent prostate cancer. Methods: Nine patients with PSMA-positive lesions on PET/CT received ^99mTc-MIP-1404 (median, 747 MBq; interquartile range [IQR], 710-764 MBq) 17.2 h (IQR, 16.9-17.5 h) before SPECT/CT and 22.3 h (IQR, 20.8-24.0 h) before RGS. Results: Seventeen PSMA-positive lesions were detected on PET/CT (median short-axis diameter, 4 mm; IQR, 3-6 mm; median SUV_max, 8.9; IQR, 5.2-12.6). Nine of 17 (52.9%) were visible on SPECT/CT (median SUV_max, 13.8; IQR, 8.0-17.9). Except for 2 foci, all PET/CT-positive findings demonstrated intraoperative count rates above the background level (median count, 31; IQR, 17-89) and were lymph node metastases. Moreover, PSMA-RGS identified 2 additional metastases compared with PET/CT. Prostate-specific antigen values decreased after RGS in 6 of 9 patients (67%). Conclusion: PSMA-RGS with ^99mTc-MIP-1404 identified lymph node metastases in all patients, including 2 additional lesions compared with PET/CT.

The prostate-specific membrane antigen (PSMA) is a type II transmembrane glycoprotein that is highly expressed in the malignant human prostate epithelium. Therefore, PSMA has emerged as a very attractive target for developing radiopharmaceuticals for the diagnosis, e.g., by positron emission tomography (PET) imaging, and radiotherapy of prostate cancer. The aim of this study was to develop ¹⁸F-labeled PSMA ligands bearing different ¹⁸F-glycosyl moieties to study the effect on the in vivo clearance behavior of radiotracers in addition to their tumor binding ability. Therefore, we applied click chemistry-based ¹⁸F-fluoroglcosylation using 2-deoxy-2-[¹⁸F]fluoroglucosyl azide or 6-deoxy-6-[¹⁸F]fluoroglucosyl azide as prosthetic groups for the radiosynthesis of the ¹⁸F-fluoroglycosylated glutamate-urea-lysine-based PSMA inhibitors 2-[¹⁸F]FGlc-PSMA ([¹⁸F]7) and 6-[¹⁸F]FGlc-PSMA ([¹⁸F]8). The PSMA inhibitory potencies were determined by competitive radioligand binding assays using ^99mTc-MIP-1404 and PSMA-expressing PC-3 PIP cells, revealing moderate PSMA inhibitory potencies for [¹⁸F]7 (IC₅₀ = 234 nM) and [¹⁸F]8 (IC₅₀ = 59 nM). Biodistribution and small-animal PET studies were performed using PSMA-positive PC-3 PIP and PSMA-negative PC-3 tumor-bearing nude mice. PSMA inhibitors [¹⁸F]7 and [¹⁸F]8 were obtained in high radioactivity yields of 19-22% (nondecay-corrected, referred to [¹⁸F]fluoride) and with molar activities of 71-136 GBq/μmol. In the biodistribution studies, the uptake levels of [¹⁸F]7 and [¹⁸F]8 in PC-3 PIP tumors were 13 ± 3%ID/g and 6 ± 5%ID/g at 60 min p.i., respectively. PSMA-negative PC-3 tumors and all other tissues had negligible low uptake values. Interestingly, [¹⁸F]7 had high uptake in the kidneys, with remarkable retention from 30 to 60 min p.i. (74 to 72%ID/g). In contrast, [¹⁸F]8 revealed a low uptake of 7.5%ID/g in the kidneys at 30 min p.i. and was rapidly cleared through the kidney (0.9%ID/g at 120 min p.i.). In direct comparison to a ⁶⁸Ga-PSMA-11 PET scan of the same mouse, [¹⁸F]7 and [¹⁸F]8 showed 2- to 3-fold higher uptake values in PC-3 PIP tumors. Both radiotracers were solely cleared via the kidneys and not via the hepatobiliary pathway. The regional kidney distribution pattern of the tracers in the kidneys revealed that ⁶⁸Ga-PSMA-11 and 2-[¹⁸F]FGlc-PSMA([¹⁸F]7) mainly accumulated in the cortex of the kidneys, whereas 6-[¹⁸F]FGlc-PSMA([¹⁸F]8) showed a 10-fold lower kidney uptake with accumulation in the inner medulla or pelvis of the kidneys. Overall, the developed 6-fluoroglucosyl derivative [¹⁸F]8, with its considerably low kidney uptake and fast clearance, demonstrated high uptake in PSMA-positive tumors in vivo. This candidate could, therefore, be valuable for translation into the clinic.