Fully automated radiolabeling of [68Ga]Ga-EMP100 targeting c-MET for PET-CT clinical imaging.

BACKGROUND: c-MET is a transmembrane receptor involved in many biological processes and contributes to cell proliferation and migration during cancer invasion process. Its expression is measured by immunehistochemistry on tissue biopsy in clinic, although this technique has its limitations. PET-CT could allow in vivo mapping of lesions expressing c-MET, providing whole-body detection. A number of radiopharmaceuticals are under development for this purpose but are not yet in routine clinical use. EMP100 is a cyclic oligopeptide bound to a DOTA chelator, with nanomolar affinity for c-MET. The aim of this project was to develop an automated method for radiolabelling the radiopharmaceutical [68Ga]Ga-EMP100. RESULTS: The main results showed an optimal pH range between 3.25 and 3.75 for the complexation reaction and a stabilisation of the temperature at 90 °C, resulting in an almost complete incorporation of gallium-68 after 10 min of heating. In these experiments, 90 µg of EMP-100 peptide were initially used and then lower amounts (30, 50, 75 µg) were explored to determine the minimum required for sufficient synthesis yield. Radiolysis impurities were identified by radio-HPLC and ascorbic acid and ethanol were used to improve the purity of the compound. Three batches of [68Ga]Ga-EMP100 were then prepared according to the optimised parameters and all met the established specifications. Finally, the stability of [68Ga]Ga-EMP100 was assessed at room temperature over 3 h with satisfactory results in terms of appearance, pH, radiochemical purity and sterility. CONCLUSIONS: For the automated synthesis of [68Ga]Ga-EMP100, the parameters of pH, temperature, precursor peptide content and the use of adjuvants for impurity management were efficiently optimised, resulting in the production of three compliant and stable batches according to the principles of good manufacturing practice. [68Ga]Ga-EMP100 was successfully synthesised and is now available for clinical development in PET-CT imaging.

Diagnostic performance and impact on patient management of [68Ga]Ga-DOTA-TOC PET/CT in colorectal neuroendocrine tumors derived from hindgut.

The main purpose of this retrospective study was to determine the diagnostic performance of [68Ga]Ga-DOTA-D-Phe1-Try3-octreotide(DOTA-TOC) positron emission tomography/computed tomography (PET/CT) in patients with well-differentiated colorectal Neuroendocrine Tumours (NETs) originating from the hindgut. The other aims were to assess the impact of the examination on patient management and to analyze the results of 2-[18F]FDG and/or 6-[18F]FDOPA PET/CT when they were performed. [68Ga]Ga-DOTA-TOC PET/CT and clinical data from 30 patients with biopsy-proven well-differentiated NETs originating from the hindgut were retrospectively reviewed and analyzed by comparing the [68Ga]Ga-DOTA-TOC PET/CT findings with pathological and/or follow-up data. We also compared the [68Ga]Ga-DOTA-TOC PET/CT results with 2-[18F]FDG and/or 6-[18F]FDOPA PET/CT results in 6 patients. The impact on management was determined in hindsight by comparing the patient management decided before and after the TEP examination based on data from multidisciplinary team meetings. On a patient basis, [68Ga]Ga-DOTA-TOC PET/CT was accurate in 30 of the 30 examinations. [68Ga]Ga-DOTA-TOC PET/CT correctly identified the primary tumor in all patients with primary tumors not resected before the examination and allowed the detection of unexpected distant metastases in 36% of the patients referred for initial staging. [68Ga]Ga-DOTA-TOC PET/CT findings affected patient management in 57% of cases with generally major intermodality changes. Intraindividual comparison of the results of the different PET radiopharmaceuticals showed a clear superiority of [68Ga]Ga-DOTA-TOC PET/CT considering both the number of lesions and the intensity of uptake. [68Ga]Ga-DOTA-TOC PET/CT is an accurate imaging modality for the assessment of well-differentiated colorectal NETs that highly impact patient management. Thus, we suggest that [68Ga]Ga-DOTA-TOC PET/CT be employed as a first choice for the assessment of these tumors in nuclear medicine.

Role of 68Ga-DOTATOC PET/CT in Insulinoma According to 3 Different Contexts: A Retrospective Study.

OBJECTIVE: The aim of this study was to assess the performance of 68Ga-DOTATOC PET/CT in the detection and extension of insulinomas according to 3 different contexts: sporadic benign, sporadic metastatic, and multiple endocrine neoplasia type 1 (MEN1). PATIENTS AND METHODS: The data of 71 adult patients who underwent 68Ga-DOTATOC PET/CT for suspected or confirmed sporadic insulinoma, suspicion of insulinoma in the context of MEN1, follow-up of metastatic insulinoma, or suspicion of recurrence of insulinoma were retrospectively analyzed. Pathological examination or strong clinical and biological findings were used as standards of truth. RESULTS: For the assessment of a confirmed sporadic insulinoma in 17 patients, the sensitivity of SR-PET was 75%, including 2 patients for whom metastatic lesions had been revealed by SR-PET. For 35 patients with a suspicion of insulinoma, the sensitivity was 39%. In 10 patients followed up for metastatic insulinoma, the sensitivity was 100%. For 5 patients with a history of MEN1, interpretation of SR-PET was difficult, as 3 of them presented with multiple pancreatic uptake foci. The global sensitivity of SR-PET in all insulinomas excluding those with a MEN1 story was 64% (100% for metastatic insulinomas, 62% for benign insulinomas), with a specificity of 89%. CONCLUSIONS: 68Ga-DOTATOC PET/CT is a useful examination tool for the assessment of insulinomas in selected contexts, with very high performance for the detection and extension workup of metastatic insulinomas and high specificity for the detection of sporadic benign insulinomas. The examination should be completed with GLP-1 receptor PET when it is negative or in a MEN1 context.

Ultra-fast liquid chromatography method coupled with ultraviolet detection to quantify dimethylsulfoxide, dimethylformamide and dimethylacetamide in short half-lives radiopharmaceuticals.

Radiolabelling with short half-lives radionuclides (e.g., fluorine-18 and carbon-11) must be as efficient and as fast as possible. Nucleophilic radiofluorinations and radiomethylations are conducted in polar aprotic solvents, such as dimethylsulfoxyde (DMSO), N,N-dimethylformamide (DMF) and N,N-dimethylacetamide (DMA), at high temperature. Those solvents are classified as toxic according to the ICH guidelines and must be evaluated in drug such as radiopharmaceuticals. Headspace gas chromatography is the standard method for the quantification of residual solvents but is not optimized for a rapid quantification of low vapor pressure solvents such as DMSO, DMF and DMA in radiopharmaceuticals. Direct injection gas chromatography is an interesting option without incubation step but the analysis run-time remains beyond 10 min long. In consequence, we developed a very simple ultra-high performance liquid chromatography method coupled with UV detection. Following the EMA requirements, we successfully validated a 3-min run-time analysis for quantification of three solvents in short half-lives radiopharmaceuticals. We currently use this method for the quality control of radiopharmaceuticals produced in our PET center.

Restaging the Biochemical Recurrence of Prostate Cancer with [68Ga]Ga-PSMA-11 PET/CT: Diagnostic Performance and Impact on Patient Disease Management.

BACKGROUND: Detection rates of [68Ga]Ga-PSMA-11 PET/CT on the restaging of prostate cancer (PCa) patients presenting with biochemical recurrence (BCR) have been well documented, but its performance and impact on patient management have not been evaluated as extensively. METHODS: Retrospective analysis of PCa patients presenting with BCR and referred for [68Ga]Ga-PSMA-11 PET/CT. Pathological foci were classified according to six anatomical sites and evaluated with a three-point scale according to the uptake intensity. The impact of [68Ga]Ga-PSMA-11 PET/CT was defined as any change in management that was triggered by [68Ga]Ga-PSMA-11 PET/CT. The existence of a PCa lesion was established according to a composite standard of truth based on all clinical data available collected during the follow-up period. RESULTS: We included 294 patients. The detection rate was 69%. Per-patient sensitivity and specificity were both 70%. Patient disease management was changed in 68% of patients, and [68Ga]Ga-PSMA-11 PET/CT impacted this change in 86% of patients. The treatment carried out on patient was considered effective in 89% of patients when guided by [68Ga]Ga-PSMA-11 PET/CT versus 61% of patients when not guided by [68Ga]Ga-PSMA-11 PET/CT (p < 0.001). CONCLUSIONS: [68Ga]Ga-PSMA-11 PET/CT demonstrated high performance in locating PCa recurrence sites and impacted therapeutic management in nearly two out of three patients.

Comparison of 51Cr-EDTA and 99mTc-DTPA for glomerular filtration rate measurement.

PURPOSE: The production of 51Cr-labelled ethylenediaminetetraacetic acid (51Cr-EDTA), a validated and widely used radio-isotopic tracer for glomerular filtration rate (GFR) measurement in Europe, was recently halted by the manufacturer. Technetium-99m-diethylenetriaminepentaacetic acid (99mTc-DTPA) clearance has so far mostly been restricted to assessment of separate renal function by scintigraphy, but scarcely used and validated for GFR measurement. We compared the performances of 51Cr-EDTA and 99mTc-DTPA for GFR and extracellular fluid measurement. METHODS: In a multi-centre prospective study, 51Cr-EDTA and 99mTc-DTPA were simultaneously injected into 88 patients, and their urinary and plasma clearances, as well as their volumes of distribution, were measured during seven 30-min periods after a 90-min equilibrium time. RESULTS: Mean age was 52.2 ± 14.5 years, 59% were men. Urinary clearances of 51Cr-EDTA and 99mTc-DTPA were 64.1 ± 27.6 and 66.1 ± 28.0 mL/min, respectively, with a mean bias of 2.00 ± 2.25 mL/min, an accuracy within 10% of 95% [95% CI 91-99], and a coefficient of determination (R2) of 0.994. Plasma clearances of 51Cr-EDTA and 99mTc-DTPA were 66.1 ± 25.8 and 68.1 ± 26.6 mL/min, respectively, with a mean bias of 1.96 ± 3.32 mL/min, an accuracy within 10% of 91% [95% CI 85-97] and a R2 of 0.985. Distribution volumes were 17.3 ± 4.6 L for 51Cr-EDTA and 16.6 ± 4.6 L for 99mTc-DTPA (R2 0.930). CONCLUSION: The accuracy and precision of 99mTc-DTPA clearance, compared to 51Cr-EDTA clearance, was excellent for both urinary and plasma clearance methods, despite an approximate 2 mL/min overestimation, showing that the tracer is a reliable alternative to 51Cr-EDTA for GFR measurement.

A comparative study of peptide-based imaging agents [68Ga]Ga-PSMA-11, [68Ga]Ga-AMBA, [68Ga]Ga-NODAGA-RGD and [68Ga]Ga-DOTA-NT-20.3 in preclinical prostate tumour models.

INTRODUCTION: Peptide-based imaging agents targeting prostate-specific membrane antigen (PSMA) have revolutionized the evaluation of biochemical recurrence of prostate cancer (PCa) but lacks sensitivity at very low serum prostate specific antigen (PSA) levels. Once recurrence is suspected, other positron emission tomography (PET) radiotracers could be of interest to discriminate between local and distant relapse. We studied [18F]fluorodeoxyglucose ([18F]FDG) targeting glucose metabolism, [18F]fluorocholine ([18F]FCH) targeting membrane metabolism and peptide-based imaging agents [68Ga]Ga-PSMA-11, [68Ga]Ga-AMBA, [68Ga]Ga-NODAGA-RGD and [68Ga]Ga-DOTA-NT-20.3 targeting PSMA, gastrin releasing peptide receptor (GRPr), αvß3 integrin and neurotensin type 1 receptor (NTSR1) respectively, in different PCa tumour models. METHODS: Mice were xenografted with 22Rv1, an androgen-receptor (AR)-positive, PCa cell line that expresses PSMA and PC3, an AR-negative one that does not express PSMA. PET imaging using the different radiotracers was performed sequentially and the uptake characteristics compared to one other. NTSR1 and PSMA expression levels were analysed in tumours by immunohistochemistry. RESULTS: [18F]FDG displayed low but sufficient uptake to visualize PC3 and 22Rv1 derived tumours. We also observed a low efficacy of [18F]FCH PET imaging and a low [68Ga]Ga-NODAGA-RGD tumour uptake in those tumours. As expected, an elevated tumour uptake was obtained for [68Ga]Ga-PSMA-11 in 22Rv1 derived tumour although no uptake was measured in the androgen independent cell line PC3, derived from a bone metastasis of a high-grade PCa. Moreover, in PC3 cell line, we obtained good tumour uptake, high tumour-to-background contrast using [68Ga]Ga-AMBA and [68Ga]Ga-DOTA-NT-20.3. Immunohistochemistry analysis confirmed high NTSR1 expression in PC3 derived tumours and conversely high PSMA expression in 22Rv1 derived tumours. CONCLUSION: PET imaging using [68Ga]Ga-AMBA and [68Ga]Ga-DOTA-NT-20.3 demonstrates that GRPr and NTSR1 could represent viable alternative targets for diagnostic or therapeutic applications in PCa with limited PSMA expression levels. More preclinical and clinical studies will follow to explore this potential. ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT: Peptide-based imaging agents targeting PSMA represent a major progress in the evaluation of biochemical recurrence of PCa but sometimes yield false negative results in some lesions. Continuing efforts have thus been made to evaluate other radiotracers. Our preclinical results suggest that [68Ga]labelled bombesin and neurotensin analogues could serve as alternative PET radiopharmaceuticals for diagnostic or therapy in cases of PSMA-negative PCa.