Development of in-House Synthesis and Quality Control of [99mTc]Tc-PSMA-I&S

Abstract

Many radioactive PSMA inhibitory substances have already been developed for PET diagnostics and therapy of prostate cancer. Because PET radionuclides and instrumentation may not be available, technetium-99 m labelled tracers can be considered as a diagnostic alternative. A suitable tracer is [99mTc]Tc-PSMA-I&S, primarily developed for radio-guided surgery, which has been identified for diagnostics of prostate cancer. However, there is no commercial kit approved for the preparation of [99mTc]Tc-PSMA-I&S on the market. This work presents an automated process for the synthesis of [99mTc]Tc-PSMA-I&S concerning good manufacturing practice (GMP). We used a Scintomics GRP 4 V module, with the SCC software package for programming sequences for this development. The optimum reaction conditions were evaluated in preliminary experiments. The pH of the reaction solution was found to be crucial for the radiochemical yield and radiochemical purity. The validation of [99mTc]Tc-PSMA-I&S (n = 3) achieved a stable radiochemical yield of 58.7 ± 1.5% and stable radiochemical purities of 93.0 ± 0.3%. The amount of free [99mTc]TcO4− in the solution and reduced hydrolysed [99mTc]TcO2 was <2%. Our automated preparation of [99mTc]Tc-PSMA-I&S has shown reliability and applicability in the clinical setting.

Preparation, Biological Evaluation, and First-in-Human Single-Photon Emission Computed Tomography (SPECT) Study of 99mTc-Labeled Prostate-Specific Membrane Antigen (PSMA)-Targeted Radiotracers Containing Triazole with Reduced Kidneys Accumulation

“…8 However, it was prepared in the presence of the [ 99m Tc(CO) 3 (H2O) 3 ] + has been explored in a kit formulation for PSMA-targeted radioguided surgery, which is available for routine production and entered a phase II study (NCT04832958). 17 This promising agent has several shortcomings, including slow washout from the blood pool and prolonged retention in the kidneys, liver, and intestines. As a bifunctional chelator of 99m Tc, HYNIC is considered an efficient labeling platform for the formation of stable 99m Tc complexes with high RCY.…”

“…However, it was prepared in the presence of the [ 99m Tc­(CO) 3 (H2O) 3 ] + intermediate and purified by radio-HPLC, which is an obstacle to its wider use in clinical practice. Based on the [ 99m Tc]­[TcO] 3+ core, [ 99m Tc]­Tc-PSMA-I&S (imaging and surgery) has been explored in a kit formulation for PSMA-targeted radioguided surgery, which is available for routine production and entered a phase II study (NCT04832958) . This promising agent has several shortcomings, including slow washout from the blood pool and prolonged retention in the kidneys, liver, and intestines.…”

“…Finally, many 99m Tc-labeled radiopharmaceuticals can be prepared from lyophilized kit formulations for clinical application via simple and reproducible labeling procedures. To date, many 99m Tc-labeled PSMA agents, such as [ 99m Tc]­Tc-MIP-1404, [ 99m Tc]­Tc-PSMA-I&S, [ 99m Tc]­Tc-EDDA/HYNIC-iPSMA, [ 99m Tc]­Tc-PSMA-T4, and [ 99m Tc]­Tc-HYNIC-ALUG, have been developed in clinical trials to evaluate their potential for PCa diagnosis. However, the reported studies have several drawbacks, such as requiring multistep radiosynthesis, requiring postlabeling purification, and exhibiting slow clearance from the hepatobiliary and intestinal tracts, which limit the clinical application and accurate detection of metastatic lesions.…”

Pyrazolopyridine Ligands in Transition-Metal-Catalyzed C–C and C–Heteroatom Bond-Forming Reactions

“…Similarly, (de)hydrogenation and (de)hydration are beyond the scope of this review, and readers are directed to a recently published excellent review for these transformations. 11 Additionally, while N,C′-chelation of these heterocycles is feasible, the discussion is centered around N,N′-chelation, which is crucial for most of the reported catalytic activities.…”

“…Moreover, the potential of PzPy ligands has been explored in hydrogenation and dehydrogenation reactions. 11 Nonetheless, their application in facilitating the formation of C-C and C-heteroatom bonds has only come to the forefront in recent years.…”