Publications by authors named "Michael Meisenheimer"

11 Publications

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DOTA-ZOL: A Promising Tool in Diagnosis and Palliative Therapy of Bone Metastasis-Challenges and Critical Points in Implementation into Clinical Routine.

Molecules 2020 Jun 30;25(13). Epub 2020 Jun 30.

Positronpharma SA, Rancagua 878, Providencia 7500921, Chile.

The novel compound 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-ZOL (DOTA-conjugated zoledronic acid) is a promising candidate for the diagnosis and therapy of bone metastasis. The combination of the published methodology for this bisphosphonate with pharmaceutical and regulatory requirements turned out to be unexpectedly challenging. The scope of this work is the presentation and discussion of problems encountered during this process. Briefly, the radiolabelling process and purification, as well as the quality control published, did not meet the expectations. The constant effort setting up an automated radiolabelling procedure resulted in (a) an enhanced manual method using coated glass reactors, (b) a combination of three different reliable radio thin-layer chromatography (TLC) methods instead of the published and (c) a preliminary radio high-pressure liquid chromatography (HPLC) method for identification of the compound. Additionally, an automated radiolabelling process was developed, but it requires further improvement, e.g., in terms of a reactor vessel or purification of the crude product. The published purification method was found to be unsuitable for clinical routine, and an intense screening did not lead to a satisfactory result; here, more research is necessary. To sum up, implementation of DOTA-ZOL was possible but revealed a lot of critical points, of which not all could be resolved completely yet.
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http://dx.doi.org/10.3390/molecules25132988DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7412164PMC
June 2020

Manual vs automated Ga-radiolabelling-A comparison of optimized processes.

J Labelled Comp Radiopharm 2020 04 26;63(4):162-173. Epub 2020 Feb 26.

PositronPharma, Santiago de Chile, Chile.

A critical factor for clinical practice is the production of Ga radiopharmaceuticals manufactured manually or through an automated procedure. Ga radiopharmaceuticals are often prepared manually, although this method can lead to an increased operator's radiation dose and potential variability within production. The present work compares Ga-radiolabelling (PSMA-11; DOTA-TOC) utilizing a cassette module (GAIA; Elysia-Raytest; Germany) with a manual setup for routine clinical production with regard to process reliability and reproducibility.
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http://dx.doi.org/10.1002/jlcr.3821DOI Listing
April 2020

Biodistribution and post-therapy dosimetric analysis of [Lu]Lu-DOTA in patients with osteoblastic metastases: first results.

EJNMMI Res 2019 Nov 28;9(1):102. Epub 2019 Nov 28.

Department of Nuclear Medicine, University Medical Center Bonn, Bonn, Germany.

Background: Preclinical biodistribution and dosimetric analysis of [Lu]Lu-DOTA suggest the bisphosphonate zoledronate as a promising new radiopharmaceutical for therapy of bone metastases. We evaluated biodistribution and normal organ absorbed doses resulting from therapeutic doses of [Lu]Lu-DOTA in patients with metastatic skeletal disease.

Method: Four patients with metastatic skeletal disease (age range, 64-83 years) secondary to metastatic castration-resistant prostate carcinoma or bronchial carcinoma were treated with a mean dose of 5968 ± 64 MBq (161.3 mCi) of [Lu]Lu-DOTA. Biodistribution was assessed with serial planar whole body scintigraphy at 20 min and 3, 24, and 167 h post injection (p.i.) and blood samples at 20 min and 3, 8, 24, and 167 h p.i. Percent of injected activity in the blood, kidneys, urinary bladder, skeleton, and whole body was determined. Bone marrow self-dose was determined by an indirect blood-based method. Urinary bladder wall residence time was calculated using Cloutier's dynamic urinary bladder model with a 4-h voiding interval. OLINDA/EXM version 2.0 (Hermes Medical Solutions, Stockholm, Sweden) software was used to determine residence times in source organs by applying biexponential curve fitting and to calculate organ absorbed dose.

Results: Qualitative biodistribution analysis revealed early and high uptake of [Lu]Lu-DOTA in the kidneys with fast clearance showing minimal activity by 24 h p.i. Activity in the skeleton increased gradually over time. Mean residence times were found to be highest in the skeleton followed by the kidneys. Highest mean organ absorbed dose was 3.33 mSv/MBq for osteogenic cells followed by kidneys (0.490 mSv/MBq), red marrow (0.461 mSv/MBq), and urinary bladder wall (0.322 mSv/MBq). The biodistribution and normal organ absorbed doses of [Lu]Lu-DOTA are consistent with preclinical data.

Conclusion: [Lu]Lu-DOTA shows maximum absorbed doses in bone and low kidney doses, making it a promising agent for radionuclide therapy of bone metastasis. Further studies are warranted to evaluate the efficacy and safety of radionuclide therapy with [Lu]Lu-DOTA in the clinical setting.
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http://dx.doi.org/10.1186/s13550-019-0566-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6882969PMC
November 2019

Ethanol effects on Ga-radiolabelling efficacy and radiolysis in automated synthesis utilizing NaCl post-processing.

EJNMMI Radiopharm Chem 2019 Oct 7;4(1):26. Epub 2019 Oct 7.

PositronPharma S.A, Rancagua 878, 7500921, Providencia, Chile.

Objective: Recent studies showed that ethanol in the reaction mixture improves radiolabelling with trivalent radiometals in terms of precursor amount, reaction time, reaction temperature and radiolysis. With regard to clinical application, this effect is of practical interest in radiopharmacy. The aim of this study was to evaluate whether the positive effect of ethanol can be exploited in automated systems utilizing NaCl-post processing.

Methods: Gallium-68 was obtained from a 1.85 GBq Ge/Ga-generator. Radiolabelling was performed on an automated Ga-labelling cassette module. The standard labelling protocol was used without modifications. 0-40 vol% ethanol were added to the reaction mixture. Quality control was performed using radioHPLC and radioTLC.

Results: Utilization of additional ethanol on an automated cassette module can be achieved by adding ethanol directly to the buffer solution without further modifications of the standard procedure. Radiolysis was decreased significantly as analysed by radioHPLC.

Conclusion: It was possible to combine the positive effects of ethanol on radiolabelling efficacy and radiolysis with the standard labelling procedure of an automated cassette module system. The whole process guarantees safe preparation of highly pure Ga-peptide for clinical application.
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http://dx.doi.org/10.1186/s41181-019-0076-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6779680PMC
October 2019

Preliminary results of biodistribution and dosimetric analysis of [Ga]Ga-DOTA: a new zoledronate-based bisphosphonate for PET/CT diagnosis of bone diseases.

Ann Nucl Med 2019 Jun 15;33(6):404-413. Epub 2019 Mar 15.

Department of Nuclear Medicine, University Medical Center Bonn, Bonn, Germany.

Objective: Pre-clinical studies with gallium-68 zoledronate ([Ga]Ga-DOTA) have proposed it to be a potent bisphosphonate for PET/CT diagnosis of bone diseases and diagnostic counterpart to [Lu]Lu-DOTA and [Ac]Ac-DOTA. This study aims to be the first human biodistribution and dosimetric analysis of [Ga]Ga-DOTA.

Methods: Five metastatic skeletal disease patients (mean age: 72 years, M: F; 4:1) were injected with 150-190 MBq (4.05-5.14 mCi) of [Ga]Ga-DOTA i.v. Biodistribution of [Ga]Ga-DOTA was studied with PET/CT initial dynamic imaging for 30 min; list mode over abdomen (reconstructed as six images of 300 s) followed by static (skull to mid-thigh) imaging at 45 min and 2.5 h with Siemens Biograph 2 PET/CT camera. Also, blood samples (8 time points) and urine samples (2 time points) were collected over a period of 2.5 h. Total activity (MBq) in source organs was determined using interview fusion software (MEDISO Medical Imaging Systems, Budapest, Hungary). A blood-based method for bone marrow self-dose determination and a trapezoidal method for urinary bladder contents residence time calculation were used. OLINDA/EXM version 2.0 software (Hermes Medical Solutions, Stockholm, Sweden) was used to generate residence times for source organs, organ absorbed doses and effective doses.

Results: High uptake in skeleton as target organ, kidneys and urinary bladder as organs of excretion and faint uptake in liver, spleen and salivary glands were seen. Qualitative and quantitative analysis supported fast blood clearance, high bone to soft tissue and lesion to normal bone uptake with [Ga]Ga-DOTA. Urinary bladder with the highest absorbed dose of 0.368 mSv/MBq presented the critical organ, followed by osteogenic cells, kidneys and red marrow receiving doses of 0.040, 0.031 and 0.027 mSv/MBq, respectively. The mean effective dose was found to be 0.0174 mSv/MBq which results in an effective dose of 2.61 mSv from 150 MBq.

Conclusions: Biodistribution of [Ga]Ga-DOTA was comparable to [F]NaF, [Tc]Tc-MDP and [Ga]Ga-PSMA-617. With proper hydration and diuresis to reduce urinary bladder and kidney absorbed doses, it has clear advantages over [F]NaF owing to its onsite, low-cost production and theranostic potential of personalized dosimetry for treatment with [Lu]Lu-DOTA and [Ac]Ac-DOTA.
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http://dx.doi.org/10.1007/s12149-019-01348-7DOI Listing
June 2019

Outcome and safety of rechallenge [Lu]Lu-PSMA-617 in patients with metastatic prostate cancer.

Eur J Nucl Med Mol Imaging 2019 May 24;46(5):1073-1080. Epub 2018 Nov 24.

Department of Nuclear Medicine, University Hospital Bonn, Sigmund-Freud-Str. 25, 53127, Bonn, Germany.

Background: Data are sparse regarding the feasibility of radioligand therapy (RLT) with [Lu]Lu-PSMA-617 as a retreatment. We aimed to assess the outcome and safety of rechallenge PSMA-RLT in patients with progressive prostatic cancer who previously benefited from this therapy.

Materials And Methods: Patients who received rechallenge therapy at our department from January 2015 to March 2018 were assessed. Non-haematological and haematological adverse events were evaluated from laboratory data and clinical reports and were graded according to the Common Terminology Criteria for Adverse Events (CTCAE v. 5.0). Time to prostate-specific-antigen (PSA) progression and the overall survival (OS) rate of the study patients were calculated from the date of the first rechallenge cycle. Furthermore, the OS calculated from the first cycle baseline PSMA-RLT was compared with the survival of patients who received only baseline PSMA-RLT. The response data were determined using [Ga]Ga-PSMA-PET/CT and measurements of the tumour marker PSA.

Results: Included in this retrospective study were 30 patients who were initially treated with a median of 3 cycles (range 1-5) of PSMA-RLT and were eventually retreated after a median of 6 months (range 2-26). Each patient received a median of 3 (range 1-6) rechallenge cycles. None of the patients experienced a disabling or life-threatening grade 4 adverse event according to the Common Toxicity Criteria (CTC). Grade 3 toxicity occurred in 8 patients (27%). Serious adverse events included leucopoenia (n = 2), neutropoenia (n = 1), anaemia (n = 4), thrombopenia (n = 4) and elevated renal parameters (n = 1). Irreversible adverse events occurred in 21 patients (70%). The permanent adverse events were mild/moderate (CTC grade 1/2) in 19 patients and serious (CTC grade 3) in two patients, respectively. According to PSA measurements, 75-90% of patients showed a benefit (response/stable) from the first 4 rechallenge cycles. The median OS was 12 months calculated from the first rechallenge cycle and 25 months calculated from the first cycle baseline PSMA-RLT. For comparison, the median OS in patients who received only baseline PSMA-RLT was 9 months. The difference according to the logrank test was significant: p value <0.001. Patients with a PSA decrease after the first cycle of rechallenge PSMA-RLT survived a median of 19 months, while patients with a PSA increase survived only 6 months.

Conclusion: Rechallenge prostate-specific membrane antigen (PSMA) therapy has an acceptable safety profile. The majority of the retreated patients benefited from the rechallenge therapy. Patients who showed a biochemical response achieved a longer OS compared to patients who did not respond. The median OS was significantly longer in patients after rechallenge PSMA-RLT than in patients who received only baseline PSMA-RLT.
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http://dx.doi.org/10.1007/s00259-018-4222-xDOI Listing
May 2019

Targeting glucose transport and the NAD pathway in tumor cells with STF-31: a re-evaluation.

Cell Oncol (Dordr) 2018 Oct 11;41(5):485-494. Epub 2018 Jun 11.

Neuro- and Tumor Cell Biology Group, Department of Nuclear Medicine, University of Bonn, Bonn, Germany.

Background: Targeting glucose metabolism is a promising way to interfere with tumor cell proliferation and survival. However, controversy exists about the specificity of some glucose metabolism targeting anticancer drugs. Especially the potency of STF-31 has been debated. Here, we aimed to assess the impact of the glucose transporter (GLUT) inhibitors fasentin and WZB117, and the nicotinamide phosphoribosyltransferase (NAMPT) inhibitors GMX1778 and STF-31 on tumor cell proliferation and survival, as well as on glucose uptake.

Methods: Tumor-derived A172 (glioblastoma), BHY (oral squamous cell carcinoma), HeLa (cervix adenocarcinoma), HN (head neck cancer), HT-29 (colon carcinoma) and MG-63 (osteosarcoma) cells were treated with fasentin, WZB117, GMX1778 and STF-31. Proliferation rates and cell viabilities were assessed using XTT, crystal violet and LDH assays. mRNA and protein expression of GLUT1 and NAPRT were assessed using qPCR and Western blotting, respectively. The effects of inhibiting compounds on glucose uptake were measured using [F]-fluoro-deoxyglucose uptake experiments.

Results: Stimulation of tumor-derived cells with the different inhibitors tested revealed a complex pattern, whereby proliferation inhibiting and survival reducing concentrations varied in [F]-fluoro-deoxyglucose uptake experiments more than one order of magnitude among the different cells tested. We found that the effects of GMX1778 and STF-31 could be partially abolished by (i) nicotinic acid (NA) only in nicotinic acid phosphoribosyltransferase (NAPRT) expressing cells and (ii) nicotinamide mononucleotide (NMN) in all cells tested, supporting the classification of these compounds as NAMPT inhibitors. In short-time [F]-fluoro-deoxyglucose uptake experiments the application of WZB-117 was found to lead to an almost complete uptake inhibition in all cells tested, whereas the effect of fasentin was found to be cell type dependent with a maximum value of ~35% in A172, BHY, HeLa and HT-29 cells. We also found that STF-31 inhibited glucose uptake in all cells tested in a range of 25-50%. These data support the classification of STF-31 as a GLUT inhibitor.

Conclusions: Our data reveal a dual mode of action of STF-31, serving either as a NAMPT or as a GLUT inhibitor, whereby the latter seems to be apparent only at higher STF-31 concentrations. The molecular basis of such a dual function and its appearance in compounds previously designated as NAMPT-specific inhibitors requires further investigation.
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http://dx.doi.org/10.1007/s13402-018-0385-5DOI Listing
October 2018

Prediction of Normal Organ Absorbed Doses for [177Lu]Lu-PSMA-617 Using [44Sc]Sc-PSMA-617 Pharmacokinetics in Patients With Metastatic Castration Resistant Prostate Carcinoma.

Clin Nucl Med 2018 Jul;43(7):486-491

Institute of Nuclear Chemistry, Johannes Gutenberg University Mainz, Mainz, Germany.

In vivo pharmacokinetic analysis of [Sc]Sc-PSMA-617 was used to determine the normal organ-absorbed doses that may result from therapeutic activity of [Lu]Lu-PSMA-617 and to predict the maximum permissible activity of [Lu]Lu-PSMA-617 for patients with metastatic castration-resistant prostate carcinoma.

Methods: Pharmacokinetics of [Sc]Sc-PSMA-617 was evaluated in 5 patients with metastatic castration-resistant prostate carcinoma using dynamic PET/CT, followed by 3 static PET/CT acquisitions and blood sample collection over 19.5 hours, as well as urine sample collection at 2 time points. Total activity measured in source organs by PET imaging, as well as counts per milliliter measured in blood and urine samples, was decay corrected back to the time of injection using the half-life of Sc. Afterward, forward decay correction using the half-life of Lu was performed, extrapolating the pharmacokinetics of [Sc]Sc-PSMA-617 to that of [Lu]Lu-PSMA-617. Source organs residence times and organ-absorbed doses for [Lu]Lu-PSMA-617 were calculated using OLINDA/EXM software. Bone marrow self-dose was determined with indirect blood-based method, and urinary bladder contents residence time was estimated by trapezoidal approximation. The maximum permissible activity of [Lu]Lu-PSMA-617 was calculated for each patient considering external beam radiotherapy toxicity limits for radiation absorbed doses to kidneys, bone marrow, salivary glands, and whole body.

Results: The predicted mean organ-absorbed doses were highest in the kidneys (0.44 mSv/MBq), followed by the salivary glands (0.23 mSv/MBq). The maximum permissible activity was highly variable among patients; limited by whole body-absorbed dose (1 patient), marrow-absorbed dose (1 patient), and kidney-absorbed dose (3 patients).

Conclusions: [Sc]Sc-PSMA-617 PET/CT imaging is feasible and allows theoretical extrapolation of the pharmacokinetics of [Sc]Sc-PSMA-617 to that of [Lu]Lu-PSMA-617, with the intent of predicting normal organ-absorbed doses and maximum permissible activity in patients scheduled for therapy with [Lu]Lu-PSMA-617.
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http://dx.doi.org/10.1097/RLU.0000000000002102DOI Listing
July 2018

[44Sc]Sc-PSMA-617 Biodistribution and Dosimetry in Patients With Metastatic Castration-Resistant Prostate Carcinoma.

Clin Nucl Med 2018 May;43(5):323-330

Aim: [Sc]Sc-PSMA-617 with 3.9-hour half-life, in vitro and in vivo characteristics similar to [Lu]Lu-PSMA-617 and possibility of delayed imaging after 24 hours or later, implies it to be advantageous than [ Ga]Ga-PSMA-617 for pretherapeutic dosimetric assessment for [Lu]Lu-PSMA-617 in metastatic castration-resistant prostate carcinoma (mCRPC) patients. In this study, we investigated biodistribution and radiation exposure to normal organs with [Sc]Sc-PSMA-617 in mCRPC patients.

Methods: Five mCRPC patients (mean age, 69 years) enrolled for [Lu]Lu-PSMA-617 therapy were injected with 40-62 MBq [Sc]Sc-PSMA-617 intravenously; Siemens Biograph 2 PET/CT system was used to acquire dynamic PET data (30 minutes) in list mode over the abdomen, followed by the collection of static PET/CT images (skull to mid-thigh) at 45 minutes, 2 and approximately 20 hours postinjection. Time-dependent changes in percentage activity in source organs (kidneys, bladder, salivary glands, small intestine, liver, spleen, and whole body) were determined. Bone marrow and urinary bladder contents residence time were also calculated. Source organs residence time, organ-absorbed doses, and effective doses were determined using OLINDA/EXM software.

Results: Physiological tracer uptake was seen in kidneys, liver, spleen, small intestine, urinary bladder, and salivary glands and in metastases. Kidneys with highest radiation absorbed dose of 3.19E-01 mSv/MBq were the critical organs, followed by urinary bladder wall (2.24E-01 mSv/MBq, spleen [1.85E-01], salivary glands [1.11E-01], and liver [1.07E-01] mSv/MBq). Red marrow dose was found to be 3.31E-02 mSv/MBq. The mean effective dose of 3.89E-02 mSv/MBq and effective dose of 1.95 mSv was estimated from 50 MBq (treatment planning dose) of [Sc]Sc-PSMA-617.

Conclusions: [Sc]Sc-PSMA-617 is found to be a very promising radiopharmaceutical that can be used for pre [Lu]Lu-PSMA-617 therapeutic dosimetric assessment.
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http://dx.doi.org/10.1097/RLU.0000000000002003DOI Listing
May 2018
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