Dataset Information

Towards Facile Radiolabeling and Preparation of Gallium-68-/Bismuth-213-DOTA-[Thi8, Met(O2)11]-Substance P for Future Clinical Application: First Experiences.

ABSTRACT: Substance P (SP) is a small peptide commonly known as a preferential endogenous ligand for the transmembrane neurokinin-1 receptor. Nuclear Medicine procedures currently involve radiolabeled SP derivatives in peptide radioligand endotherapy of inoperable glioblastoma. Promising clinical results sparked the demand for facile production strategies for a functionalized 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-[Thi8, Met(O2)11]-SP to allow for rapid Gallium-68 or Bismuth-213 complexation. Therefore, we provide a simple kit-like radiotracer preparation method that caters for the gallium-68 activity eluted from a SnO2 generator matrix as well as preliminary results on the adaptability to produce [213Bi]Bi-DOTA-[Thi8, Met(O2)11]SP from the same vials containing the same starting material. Following a phase of radioanalysis for complexation of gallium-68 to DOTA-[Thi8, Met(O2)11]SP and assessing the radiolabeling parameters, the vials containing appropriate kit-prototype material were produced in freeze-dried batches. The facile radiolabeling performance was tested and parameters for future human application were calculated to meet the criteria for theranostic loco-regional co-administration of activity doses comprising [68Ga]Ga-DOTA-[Thi8, Met(O2)11]SP mixed with [213Bi]Bi-DOTA-[Thi8, Met(O2)11]SP. [68Ga]Ga-DOTA-[Thi8, Met(O2)11]SP was prepared quantitatively from lyophilized starting material within 25 min providing the required molar activity (18 ± 4 GBq/µmol) and activity concentration (98 ± 24 MBq/mL), radiochemical purity (>95%) and sustained radiolabeling performance (4 months at >95% LE) as well as acceptable product quality (>95% for 120 min). Additionally, vials of the same starting materials were successfully adapted to a labeling strategy available for preparation of [213Bi]Bi-DOTA-[Thi8, Met(O2)11]SP providing sufficient activity for 1-2 human doses. The resultant formulation of [68Ga]Ga-/[213Bi]Bi-DOTA-[Thi8, Met(O2)11]SP activity doses was considered of adequate radiochemical quality for administration. This investigation proposes a simple kit-like formulation of DOTA-[Thi8, Met(O2)11]SP-a first-line investigation into a user friendly, straightforward tracer preparation that would warrant efficient clinical investigations in the future. Quantitative radiolabeling was accomplished for [68Ga]Ga-DOTA-[Thi8, Met(O2)11]SP and [213Bi]Bi-DOTA-[Thi8, Met(O2)11]SP preparations; a key requirement when addressing the specific route of catheter-assisted co-injection directly into the intratumoral cavities.

SUBMITTER: Suthiram J

PROVIDER: S-EPMC8472077 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Towards Facile Radiolabeling and Preparation of Gallium-68-/Bismuth-213-DOTA-[Thi8, Met(O2)11]-Substance P for Future Clinical Application: First Experiences.

Suthiram Janine J Ebenhan Thomas T Marjanovic-Painter Biljana B Sathekge Mike M MM Zeevaart Jan Rijn JR

Pharmaceutics 20210825 9

Substance P (SP) is a small peptide commonly known as a preferential endogenous ligand for the transmembrane neurokinin-1 receptor. Nuclear Medicine procedures currently involve radiolabeled SP derivatives in peptide radioligand endotherapy of inoperable glioblastoma. Promising clinical results sparked the demand for facile production strategies for a functionalized 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-[Thi8, Met(O2)11]-SP to allow for rapid G ...[more]

PMID: 34575402

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Project description:Purpose of the studyGallium (Ga)-68-DOTA peptides targeting somatostatin receptors have been assessed as a valuable tool in neuroendocrine tumor imaging using positron emission tomography. However, at the moment, a specific monograph in the European Pharmacopoeia (Ph. Eur.) does exist only for Ga-68-edotreotide (DOTATOC) injection. Here, we report on the validation process of Ga-68-DOTA-Tyr3-octreotate (DOTATATE) cassette-based production and quality control (QC).Materials and methodsPreparation of Ga-68-DOTATATE was performed according to the current European Union-good manufacturing practices, the current good radiopharmacy practice, the Ph. Eur., and the guidelines on validation of analytical methods for radiopharmaceuticals. Process was validated via three consecutive production runs to ensure that the methods are reproducible and reliable in routine use. The QC tests for Ga-68-DOTATATE were radiochemical purity (RCP - high-pressure liquid chromatography [HPLC]), radiochemical impurities 68Ga3+ (HPLC and instant thin layer chromatography [ITLC]), chemical purity (HPLC and gas chromatography [GC]), pH (pH-strips), radionuclidic purity (principal γ-photon), germanium-breakthrough (68Ge-content), Ga-68 half-life (γ-ray spectrometry), and sterility/endotoxin assay.ResultsRadiolabeling procedure of Ga-68-DOTATATE fits all the applicable Ph. Eur. specifications. RCP measured via ITLC was >99% in the three validation batches. HPLC-measured RCP resulted 99.45%, 99.78%, and 99.75%. Germanium-breakthrough was far below the recommended level established in the Ph. Eur. Ga-68-DOTATOC injection (#2482). Residual ethanol tested with GC was less than 10%. All the batches were tested for endotoxin content, which always resulted lower than 17.5 EU/ml. All preparations passed the sterility tests. pH of the final product was 7 in all samples.ConclusionGa-68-DOTATATE fulfilled all the pre-set QCs and release criteria in the batches considered for this validation study. The results demonstrated a batch-to-batch reproducibility, ensuring that synthesis process leads to the expected final product in terms of yield, quality, reliability, safety, and efficacy.

Project description:ObjectivePancreatic neuroendocrine tumours (panNETs) arise sporadically or as part of a genetic predisposition syndrome. CT/MRI, endoscopic ultrasonography and functional imaging using Octreoscan localise and stage disease. This study aimed to evaluate the complementary role of 68Gallium (68Ga)-DOTA PET/CT in managing patients with panNETs.DesignA retrospective study conducted across three tertiary UK NET referral centres.MethodsDemographic, clinical, biochemical, cross-sectional and functional imaging data were collected from patients who had undergone a 68Ga-DOTA PET/CT scan for a suspected panNET.ResultsWe collected data for 183 patients (97 male): median (SD) age 63 (14.9) years, 89.1 vs. 9.3% (n=163 vs. 17) alive vs. dead (3 data missing), 141 sporadic vs. 42 familial (MEN1, n=36; 85.7%) panNETs. Non-functional vs. functional tumours comprised 73.2 vs. 21.3% (n=134 vs. 39) (10 missing). Histological confirmation was available in 89% of individuals (n=163) but tumour grading (Ki67 classiifcation) was technically possible only in a smaller cohort (n=143): grade 1, 50.3% (n=72); grade 2, 46.2% (n=66) and grade 3, 3.5% (n=5) (40 histopathological classification either not technically feasible or biopsy not perfomed). 60.1% (n=110) were localised, 14.2% (n=26) locally advanced and 23.5% (n=43) metastatic (4 missing). 224 68Ga-DOTA PET/CT scans were performed in total for: diagnosis/staging 40% (n=88), post-operative assessment/clinical surveillance 53% (n=117) and consideration of peptide receptor radionuclide therapy (PRRT) 8% (n=17) (2 missing). PET/CT results confirmed other imaging findings (53%), identified new disease sites (28.5%) and excluded suspected disease (5%). Overall, 68Ga-DOTA PET/CT imaging findings provided additional information in 119 (54%) patients and influenced management in 85 (39%) cases.Conclusion68Ga-DOTA PET/CT imaging more accurately stages and guides treatment in patients with sporadic/familial panNETs with newly diagnosed/recurrent disease.

Project description:Purpose[18F]Fluorodeoxyglucose (FDG) is widely used in PET/CT imaging to detect large vessel vasculitis in giant cell arteritis (GCA), but its performance is suboptimal in patients receiving glucocorticoids. We aimed to compare [68Ga]Ga-HA-DOTA-TATE, a somatostatin 2-analogue tracer, to [18F]FDG in a pilot study of patients with GCA.MethodsEight patients with active GCA were prospectively, sequentially scanned with both [18F]FDG PET/CT and [68Ga]Ga-HA-DOTA-TATE PET/CT imaging. Images were evaluated by 2 blinded nuclear medicine specialists. Tracer uptake was assessed in 8 vascular territories using SUVmax, and target-background ratios (TBR) were calculated using both right atrium (TBRRA) and liver mean (TBRliver). Mean SUVmax and TBR of individual vascular territories and index vessels were compared.ResultsThe patient median age was 71.5 years (range 64-82), and 4 (50%) were women. Active vasculitis (≥ grade 2 visual uptake in large vessels) was present in 62.5% of [18F]FDG scans. [18F]FDG scans had higher RA background activity than [68Ga]Ga-HA-DOTA-TATE (mean RA SUVmean 1.88 vs. 0.36, p < 0.001), while [68Ga]Ga-HA-DOTA-TATE had a significantly higher liver uptake (mean liver SUVmean 7.54 vs. 2.39, p < 0.001). Vascular uptake (as measured by both SUVmax and TBRliver) was significantly higher in [18F]FDG than [68Ga]Ga-HA-DOTA-TATE scans in every vascular territory (p < = 0.05 for all comparisons), including index vessels (SUVmax 4.04 vs. 1.91, p = 0.01, TBRliver 1.73 vs. 0.27, p < 0.001).ConclusionIn this pilot study of patients with active GCA, the arterial uptake of [68Ga]Ga-HA-DOTA-TATE was lower and less conspicuous compared to [18F]FDG. While further evaluation in larger cohorts is needed, a clear advantage of [68Ga]Ga-HA-DOTA-TATE over [18F]FDG for detecting vascular inflammation in GCA was not identified. TRIAL REGISTRATION, CLINICALTRIALS.GOV: NCT03812302, registered 2019-01-18, URL: https://clinicaltrials.gov/search?cond=dotatate%20%26;term=giant%20cell%20arteritis .

Dataset Information

Towards Facile Radiolabeling and Preparation of Gallium-68-/Bismuth-213-DOTA-[Thi8, Met(O2)11]-Substance P for Future Clinical Application: First Experiences.

Publications

Towards Facile Radiolabeling and Preparation of Gallium-68-/Bismuth-213-DOTA-[Thi<sup>8</sup>, Met(O<sub>2</sub>)<sup>11</sup>]-Substance P for Future Clinical Application: First Experiences.

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