Publications by authors named "Stephanie Robu"

11 Publications

  • Page 1 of 1

Imaging of cardiac fibroblast activation in a patient after acute myocardial infarction using Ga-FAPI-04.

J Nucl Cardiol 2021 Apr 15. Epub 2021 Apr 15.

Department of Nuclear Medicine, Klinikum rechts der Isar, Technical University of Munich, 81675, Munich, Germany.

Our previous study has demonstrated the feasibility of noninvasive imaging of fibroblast activation protein (FAP)-expression after myocardial infarction (MI) in MI-territory in a rat model with Ga-FAPI-04-PET. In the current extended clinical case, we sought to delineate cardiac uptake of Ga-FAPI-04 in a patient after MI with clinical indication for the evidence of fibroblast activation. Carcinoma patients without cardiac disease underwent Ga-FAPI-04-PET/CT as control. The patient with one-vessel disease underwent dynamic Ga-FAPI-04-cardiac-PET/CMR for 60 minutes. Correlation of cardiac Ga-FAPI-04 uptake with clinical findings, ECG, echocardiography, coronary-arteriography and enhanced cardiac-MRI with T1 MOLLI and ECV mapping were performed. No uptake was found in normal myocardium and in mature scar. A focal intense Ga-FAPI-04 uptake with continuous wash-out in the infarct territory of coronary occlusion correlating with T1 and ECV mapping was observed. The uptake of Ga-FAPI-04 extends beyond the actual infarcted area and overestimates the infarct size as confirmed by follow-up CMR.
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http://dx.doi.org/10.1007/s12350-021-02603-zDOI Listing
April 2021

Synthesis and Preclinical Evaluation of a Ga-Labeled Adnectin, Ga-BMS-986192, as a PET Agent for Imaging PD-L1 Expression.

J Nucl Med 2021 Sep 30;62(9):1228-1234. Epub 2021 Jan 30.

Department of Nuclear Medicine, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.

Blocking the interaction of the immune checkpoint molecule programmed cell death protein-1 and its ligand, PD-L1, using specific antibodies has been a major breakthrough for immune oncology. Whole-body PD-L1 expression PET imaging may potentially allow for a better prediction of response to programmed cell death protein-1-targeted therapies. Imaging of PD-L1 expression is feasible by PET with the adnectin protein F-BMS-986192. However, radiofluorination of proteins such as BMS-986192 remains complex and labeling yields are low. The goal of this study was therefore the development and preclinical evaluation of a Ga-labeled adnectin protein (Ga-BMS-986192) to facilitate clinical trials. Ga labeling of DOTA-conjugated adnectin (BXA-206362) was performed in NaOAc-buffer at pH 5.5 (50°C, 15 min). In vitro stability in human serum at 37°C was analyzed using radio-thin layer chromatography and radio-high-performance liquid chromatography. PD-L1 binding assays were performed using the transduced PD-L1-expressing lymphoma cell line U-698-M and wild-type U-698-M cells as a negative control. Immunohistochemical staining studies, biodistribution studies, and small-animal PET studies of Ga-BMS-986192 were performed using PD-L1-positive and PD-L1-negative U-698-M-bearing NSG mice. Ga-BMS-986192 was obtained with quantitative radiochemical yields of more than 97% and with high radiochemical purity. In vitro stability in human serum was at least 95% after 4 h of incubation. High and specific binding of Ga-BMS-986192 to human PD-L1-expressing cancer cells was confirmed, which closely correlates with the respective PD-L1 expression level determined by flow cytometry and immunohistochemistry staining. In vivo, Ga-BMS-986192 uptake was high at 1 h after injection in PD-L1-positive tumors (9.0 ± 2.1 percentage injected dose [%ID]/g) and kidneys (56.9 ± 9.2 %ID/g), with negligible uptake in other tissues. PD-L1-negative tumors demonstrated only background uptake of radioactivity (0.6 ± 0.1 %ID/g). Coinjection of an excess of unlabeled adnectin reduced tumor uptake of PD-L1 by more than 80%. Ga-BMS-986192 enables easy radiosynthesis and shows excellent in vitro and in vivo PD-L1-targeting characteristics. The high tumor uptake combined with low background accumulation at early imaging time points demonstrates the feasibility of Ga-BMS-986192 for imaging of PD-L1 expression in tumors and is encouraging for further clinical applications of PD-L1 ligands.
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http://dx.doi.org/10.2967/jnumed.120.258384DOI Listing
September 2021

Automated synthesis of [F]Ga-rhPSMA-7/ -7.3: results, quality control and experience from more than 200 routine productions.

EJNMMI Radiopharm Chem 2021 Jan 23;6(1). Epub 2021 Jan 23.

Chair of Pharmaceutical Radiochemistry, Technical University of Munich, Walther-Meißner-Str. 3, 85748, Garching, Germany.

Introduction: The radiohybrid (rh) prostate-specific membrane antigen (PSMA)-targeted ligand [F]Ga-rhPSMA-7 has previously been clinically assessed and demonstrated promising results for PET-imaging of prostate cancer. The ligand is present as a mixture of four stereoisomers ([F]Ga-rhPSMA-7.1, - 7.2, - 7.3 and - 7.4) and after a preclinical isomer selection process, [F]Ga-rhPSMA-7.3 has entered formal clinical trials. Here we report on the establishment of a fully automated production process for large-scale production of [F]Ga-rhPSMA-7/ -7.3 under GMP conditions (EudraLex).

Methods: [F]Fluoride in highly enriched [O]HO was retained on a strong anion exchange cartridge, rinsed with anhydrous acetonitrile and subsequently eluted with a solution of [K ⊂ 2.2.2]OH in anhydrous acetonitrile into a reactor containing Ga-rhPSMA ligand and oxalic acid in DMSO. F-for-F isotopic exchange at the Silicon-Fluoride Acceptor (SiFA) was performed at room temperature, followed by dilution with buffer and cartridge-based purification. Optimum process parameters were determined on the laboratory scale and thereafter implemented into an automated synthesis. Data for radiochemical yield (RCY), purity and quality control were analyzed for 243 clinical productions (160 for [F]Ga-rhPSMA-7; 83 for [F]Ga-rhPSMA-7.3).

Results: The automated production of [F]Ga-rhPSMA-7 and the single isomer [F]Ga-rhPSMA-7.3 is completed in approx. 16 min with an average RCY of 49.2 ± 8.6% and an excellent reliability of 98.8%. Based on the different starting activities (range: 31-130 GBq, 89 ± 14 GBq) an average molar activity of 291 ± 62 GBq/μmol (range: 50-450 GBq/μmol) was reached for labeling of 150 nmol (231 μg) precursor. Radiochemical purity, as measured by radio-high performance liquid chromatography and radio-thin layer chromatography, was 99.9 ± 0.2% and 97.8 ± 1.0%, respectively.

Conclusion: This investigation demonstrates that F-for-F isotopic exchange is well suited for the fast, efficient and reliable automated routine production of F-labeled PSMA-targeted ligands. Due to its simplicity, speed and robustness the development of further SiFA-based radiopharmaceuticals is highly promising and can be of far-reaching importance for future theranostic concepts.
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http://dx.doi.org/10.1186/s41181-021-00120-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826325PMC
January 2021

First In-Human Medical Imaging with a PASylated Zr-Labeled Anti-HER2 Fab-Fragment in a Patient with Metastatic Breast Cancer.

Nucl Med Mol Imaging 2020 Apr 20;54(2):114-119. Epub 2020 Apr 20.

5Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany.

Purpose: PASylation® offers the ability to systematically tune and optimize the pharmacokinetics of protein tracers for molecular imaging. Here we report the first clinical translation of a PASylated Fab fragment (Zr∙Df-HER2-Fab-PAS) for the molecular imaging of tumor-related HER2 expression.

Methods: A patient with HER2-positive metastatic breast cancer received 37 MBq of Zr∙Df-HER2-Fab-PAS at a total mass dose of 70 μg. PET/CT was carried out 6, 24, and 45 h after injection, followed by image analysis of biodistribution, normal organ uptake, and lesion targeting.

Results: Images show a biodistribution typical for protein tracers, characterized by a prominent blood pool 6 h p.i., which decreased over time. Lesions were detectable as early as 24 h p.i. Zr∙Df-HER2-Fab-PAS was tolerated well.

Conclusion: This study demonstrates that a PASylated Fab tracer shows appropriate blood clearance to allow sensitive visualization of small tumor lesions in a clinical setting.
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http://dx.doi.org/10.1007/s13139-020-00638-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7198682PMC
April 2020

Molecular Imaging of Fibroblast Activity After Myocardial Infarction Using a Ga-Labeled Fibroblast Activation Protein Inhibitor, FAPI-04.

J Nucl Med 2019 12 12;60(12):1743-1749. Epub 2019 Aug 12.

Department of Nuclear Medicine, Klinikum rechts der Isar der TUM, Munich, Germany.

Heart failure remains a major source of late morbidity and mortality after myocardial infarction (MI). The temporospatial presence of activated fibroblasts in the injured myocardium predicts the quality of cardiac remodeling after MI. Therefore, monitoring of activated fibroblasts is of great interest for studying cardiac remodeling after MI. Fibroblast activation protein (FAP) expression is upregulated in activated fibroblasts. This study investigated the feasibility of imaging activated fibroblasts with a new Ga-labeled FAP inhibitor (Ga-FAPI-04) for PET imaging of fibroblast activation in a preclinical model of MI. MI and sham-operated rats were scanned with Ga-FAPI-04 PET/CT (1, 3, 6, 14, 23, and 30 d after MI) and with F-FDG (3 d after MI). Dynamic Ga-FAPI-04 PET and blocking studies were performed on MI rats 7 d after coronary ligation. After in vivo scans, the animals were euthanized and their hearts harvested for ex vivo analyses. Cryosections were prepared for autoradiography, hematoxylin and eosin (H&E), and immunofluorescence staining. Ga-FAPI-04 uptake in the injured myocardium peaked on day 6 after coronary ligation. The tracer accumulated intensely in the MI territory, as identified by decreased F-FDG uptake and confirmed by PET/MR and H&E staining. Autoradiography and H&E staining of cross-sections revealed that Ga-FAPI-04 accumulated mainly at the border zone of the infarcted myocardium. In contrast, there was only minimal uptake in the infarct of the blocked rats, comparable to the uptake in the remote noninfarcted myocardium (PET image-derived ratio of infarct uptake to remote uptake: 6 ± 2). Immunofluorescence staining confirmed the presence of FAP-positive myofibroblasts in the injured myocardium. Morphometric analysis of the whole-heart sections demonstrated 3- and 8-fold higher FAP-positive fibroblast density in the border zone than in the infarct center and remote area, respectively. Ga-FAPI-04 represents a promising radiotracer for in vivo imaging of post-MI fibroblast activation. Noninvasive imaging of activated fibroblasts may have significant diagnostic and prognostic value, which could aid clinical management of patients after MI.
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http://dx.doi.org/10.2967/jnumed.119.226993DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6894377PMC
December 2019

Radiosynthesis and pre-clinical evaluation of [Ga] labeled antimicrobial peptide fragment GF-17 as a potential infection imaging PET radiotracer.

Appl Radiat Isot 2019 Jul 10;149:9-21. Epub 2019 Apr 10.

Department of Nuclear Medicine, Klinikum Rechts Der Isar, Technical University of Munich, Ismaninger Str. 22, 81675, Munich, Germany.

The antimicrobial peptide fragment GF-17 was synthesized in-house and conjugated with DOTA and measured molecular mass of DOTA-GF-17 conjugate was 2489 Da. The peptide conjugate was purified and labeled with [Ga]. The best radiolabeling efficiency (95.0%) of [Ga]DOTA-GF-17 was achieved at pH 4 with peptide conjugate amount of 20.0 nmol with 30 min of heating at 95 °C. The product remained stable for up to 3 h. The plasma protein binding and lipophilicity for [Ga]DOTA-GF-17 were 80.98% and -3.12 respectively. The uptake studies with [Ga]DOTA- GF-17 in S.aureus and P.aeruginosa bacterial strains demonstrated binding of 69.08% and 43.69% respectively. The animal bio-distribution and PET imaging studies were in agreement showing similar pattern for organs' tracer distribution and renal excretion. The tracer had rapid blood clearance and uptake in bone marrow and muscles was very low. The highest uptake of [Ga]DOTA-GF-17 was observed at 45 min and 120 min in S.aureus and P.aeruginosa infections respectively. [Ga]DOTA-GF-17 could be a promising PET tracer and holds a great scope for taking the product further to perform extensive PET studies in animal infection (using gram negative/positive strains) models to prove the diagnostic utility of this novel PET tracer for futuristic clinical applications.
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http://dx.doi.org/10.1016/j.apradiso.2019.04.008DOI Listing
July 2019

Single Lesion on Prostate-specific Membrane Antigen-ligand Positron Emission Tomography and Low Prostate-specific Antigen Are Prognostic Factors for a Favorable Biochemical Response to Prostate-specific Membrane Antigen-targeted Radioguided Surgery in Recurrent Prostate Cancer.

Eur Urol 2019 10 12;76(4):517-523. Epub 2019 Apr 12.

Department of Urology, Technical University of Munich, Munich, Germany; Martini-Klinik and Department of Urology, University Hospital Hamburg-Eppendorf, Hamburg, Germany. Electronic address:

Background: Prostate-specific membrane antigen (PSMA)-ligand positron emission tomography (PET) allows detection of metastatic prostate cancer (PC) lesions at low prostate-specific antigen (PSA) values. To facilitate their intraoperative detection during salvage surgery, we recently introduced PSMA-targeted radioguided surgery (RGS).

Objective: To describe the outcome of a large cohort of patients treated with PSMA-targeted RGS and to establish prognostic factors.

Design, Setting, And Participants: A total of 121 consecutive patients with recurrent PC as defined by PSMA-ligand PET (median PSA: 1.13ng/ml) underwent PSMA-targeted RGS.

Outcome Measurements And Statistical Analysis: The frequency of a complete biochemical response (cBR; PSA <0.2ng/ml) without additional treatment and the duration of biochemical recurrence-free survival (bRFS, time from PSMA-targeted RGS with PSA <0.2ng/ml without further treatment) were evaluated and correlated with preoperatively available clinical variables.

Results And Limitations: In almost all patients (120/121, 99%) metastatic tissue could be removed. A cBR was achieved in 77 patients (66%). The chance of cBR was highest in patients with both low preoperative PSA and a single lesion (38/45: 84%). Median bRFS was 6.4mo in the whole patient cohort and 19.8mo for patients with cBR. Significantly longer median bRFS was observed in patients with a low preoperative PSA value (p=0.004, hazard ratio 1.48, 95% confidence interval 1.13-1.93) and with a single lesion in preoperative PSMA-ligand PET (14.0 vs 2.5mo, p=0.002).

Conclusions: PSMA-targeted RGS leads to a remarkable interval of bRFS in a subset of patients. The frequency of cBR and the duration of bRFS were highest in patients with a low preoperative PSA value and a single lesion on PSMA-ligand PET.

Patient Summary: Prostate-specific membrane antigen radioguided surgery delays disease progression in selected patients with recurrent prostate cancer after radical prostatectomy. Patients with a single lesion of recurrence and a low prostate-specific antigen value had the best outcome.
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http://dx.doi.org/10.1016/j.eururo.2019.03.045DOI Listing
October 2019

Synthesis and in vitro and in vivo evaluation of urea-based PSMA inhibitors with increased lipophilicity.

EJNMMI Res 2018 Aug 22;8(1):84. Epub 2018 Aug 22.

Pharmaceutical Radiochemistry, Technische Universität München, Garching, Germany.

Background: Several radiolabeled prostate-specific membrane antigen (PSMA) inhibitors based on the lysine-urea-glutamate (KuE) motif as the pharmacophore proved to be suitable tools for PET/SPECT imaging of the PSMA expression in prostate cancer patients. PSMA I&T, a theranostic tracer developed in our group, was optimized through alteration of the peptidic structure in order to increase the affinity to PSMA and internalization in PSMA-expressing tumor cells. However, further structural modifications held promise to improve the pharmacokinetic profile.

Results: Among the investigated compounds 1-9, the PSMA inhibitors 5 and 6 showed the highest PSMA affinity (lowest IC values) after the introduction of a naphthylalanine modification. The affinity was up to three times higher compared to the reference PSMA I&T. Extended aromatic systems such as the biphenylalanine residue in 4 impaired the interaction with the lipophilic binding pocket of PSMA, resulting in a tenfold lower affinity. The IC of DOTAGA-conjugated 10 was slightly increased compared to the acetylated analog; however, efficient PSMA-mediated internalization and 80% plasma protein binding of Ga-10 resulted in effective tumor targeting and low uptake in non-target tissues of LNCaP tumor-bearing CD-1 nu/nu mice at 1 h p.i., as determined by small-animal PET imaging and biodistribution studies. For prolonged tumor retention, the plasma protein binding was increased by insertion of 4-iodo-D-phenylalanine resulting in 97% plasma protein binding and 16.1 ± 2.5% ID/g tumor uptake of Lu-11 at 24 h p.i.

Conclusions: Higher lipophilicity of the novel PSMA ligands 10 and 11 proved to be beneficial in terms of affinity and internalization and resulted in higher tumor uptake compared to the parent compound. Additional combination with para-iodo-phenylalanine in the spacer of ligand 11 elevated the plasma protein binding and enabled sustained tumor accumulation over 24 h, increasing the tumor uptake almost fourfold compared to Lu-PSMA I&T. However, high renal uptake remains a drawback and further studies are necessary to elucidate the responsible mechanism behind it.
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http://dx.doi.org/10.1186/s13550-018-0440-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6104465PMC
August 2018

Synthesis and preclinical evaluation of novel F-labeled Glu-urea-Glu-based PSMA inhibitors for prostate cancer imaging: a comparison with F-DCFPyl and F-PSMA-1007.

EJNMMI Res 2018 Apr 12;8(1):30. Epub 2018 Apr 12.

Chair of Pharmaceutical Radiochemistry, Technical University Munich, Walther-Meissner-Strasse 3, 85748, Garching, Germany.

Background: Due to its high and consistent expression in prostate cancer (PCa), the prostate-specific membrane antigen (PSMA) represents an ideal target for molecular imaging and targeted therapy using highly specific radiolabeled PSMA ligands. To address the continuously growing clinical demand for F-labeled PSMA-probes, we developed two novel Glu-urea-Glu-(EuE)-based inhibitors, EuE-k-F-FBOA (1) and EuE-k-β-a-F-FPyl (2), both with optimized linker structure and different F-labeled aromatic moieties. The inhibitors were evaluated in a comparative preclinical study with F-DCFPyl and F-PSMA-1007.

Results: Radiolabeling procedures allowed preparation of (1) and (2) with high radiochemical yields (67 ± 7 and 53 ± 7%, d.c.) and purity (> 98%). When compared with F-DCFPyl (IC = 12.3 ± 1.2 nM) and F-PSMA-1007 (IC = 4.2 ± 0.5 nM), both metabolically stable EuE-based ligands showed commensurable or higher PSMA affinity (IC = 4.2 ± 0.4 nM (1), IC = 1.1 ± 0.2 nM (2)). Moreover, 1.4- and 2.7-fold higher internalization rates were observed for (1) and (2), respectively, resulting in markedly enhanced tumor accumulation in LNCaP-tumor-bearing mice ((1) 12.7 ± 2.0% IA/g, (2) 13.0° ± 1.0% IA/g vs. 7.3 ± 1.0% IA/g (F-DCFPyl), 7.1 ± 1.5% IA/g (F-PSMA-1007), 1 h p.i.). In contrast to (1), (2) showed higher kidney accumulation and delayed clearance kinetics. Due to the high hydrophilicity of both compounds, almost no unspecific uptake in non-target tissue was observed. In contrast, due to the less hydrophilic character (logP = - 1.6) and high plasma protein binding (98%), F-PSMA-1007 showed uptake in non-target tissue and predominantly hepatobiliary excretion, whereas, F-DCFPyl exhibited pharmacokinetics quite similar to those obtained with (1) and (2).

Conclusion: Both F-labeled EuE-based PSMA ligands showed excellent in vitro and in vivo PSMA-targeting characteristics. The substantially higher tumor accumulation in mice compared to recently introduced F-PSMA-1007 and F-DCFPyl suggests their high value for preclinical studies investigating the effects on PSMA-expression. In contrast to (2), (1) seems to be more promising for further investigation, due to the more reliable F-labeling procedure, the faster clearance kinetics with comparable high tumor uptake, resulting therefore in better high-contrast microPET imaging as early as 1 h p.i.
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http://dx.doi.org/10.1186/s13550-018-0382-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5897267PMC
April 2018

Technetium-based Prostate-specific Membrane Antigen-radioguided Surgery in Recurrent Prostate Cancer.

Eur Urol 2019 04 4;75(4):659-666. Epub 2018 Apr 4.

Department of Nuclear Medicine, Technical University of Munich, Klinikum rechts der Isar, Munich, Germany.

Background: Prostate-specific membrane antigen (PSMA)-targeted positron emission tomography (PET) can visualize metastatic lesions in recurrent prostate cancer (PC). However, reliable identification of small and/or atypically localized lesions during salvage surgery procedures is challenging.

Objective: To describe the technique, feasibility, and short-term outcomes of Technetium (Tc)-based PSMA-radioguided surgery (Tc-PSMA-RGS) for removal of recurrent PC lesions.

Design, Setting, And Participants: Thirty-one consecutive patients with evidence of recurrent PC on Ga-PSMA N,N'-bis[2-hydroxy-5-(carboxyethyl)benzyl] ethylenediamine-N,N'-diacetic acid (Ga-PSMA-11) PET after radical prostatectomy undergoing Tc-PSMA-RGS were retrospectively analyzed.

Surgical Procedure: Salvage surgery with intraoperative radioguidance using a gamma probe was performed after intravenous application of Tc-PSMA investigation and surgery (mean activity 571 MBq, mean time to surgery 19.7h).

Measurements: Radioactive rating (positive vs negative) of resected tissue was compared with the findings of postoperative histopathological analysis. Best prostate-specific antigen (PSA) response without additional treatment was determined after 8-16 wk postoperatively. Biochemical recurrence- and treatment-free survival was evaluated.

Results And Limitations: In total, 132 tissue specimens were removed, of which 58 showed metastatic involvement on histological analysis. On a specimen basis, radioactive rating yielded a sensitivity of 83.6% (confidence interval [CI]: 70.9-91.5%), a specificity of 100%, and an accuracy of 93.0% (CI: 85.5-96.7%). With Tc-PSMA-RGS, all lesions visualized on preoperative Ga-PSMA-11 PET could be removed. Moreover, Tc-PSMA-RGS detected additional metastases as small as 3mm in two patients. Thirteen patients suffered from complications related to surgery (Clavien-Dindo grade 1: 12 patients; grade 3a: one patient). A PSA reduction below 0.2 ng/ml was observed in 20 patients. Thirteen patients remained biochemical recurrence free after a median follow-up of 13.8 (range: 4.6-18.3) mo. Twenty patients continued to be treatment free after a median follow-up of 12.2 (range: 5.5-18.3) mo.

Conclusions: As a new technique for surgical guidance, Tc-PSMA-RGS is feasible, and has been proved to be of high value for successful intraoperative detection and removal of metastatic lesions in PC patients scheduled for salvage surgery. Its long-term impact on outcome has to be evaluated.

Patient Summary: In this report, we evaluated a novel technique to identify metastatic lesions intraoperatively in patients with recurrent prostate cancer to facilitate surgical removal. After intravenous injection of radioactive molecules that specifically bind to prostate cancer cells that show increased expression of the prostate-specific membrane antigen, we were able to detect and remove these metastatic lesions during surgery. Following salvage surgery, 41.9% of patients remained biochemical recurrence free (median follow-up of 13.8 mo) and 64.5% continued to be treatment free (median follow-up of 12.2 mo).
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http://dx.doi.org/10.1016/j.eururo.2018.03.013DOI Listing
April 2019

Preclinical Evaluation and First Patient Application of 99mTc-PSMA-I&S for SPECT Imaging and Radioguided Surgery in Prostate Cancer.

J Nucl Med 2017 Feb 15;58(2):235-242. Epub 2016 Sep 15.

Chair of Pharmaceutical Radiochemistry, Technische Universität München, Garching, Germany.

Initial studies in patients have demonstrated the suitability of In-PSMA-I&T (In-DOTAGA-(3-iodo-y)-f-k-Sub(KuE)) (PSMA is prostate-specific membrane antigen and I&T is imaging and therapy) for radioguided surgery (RGS) of small metastatic prostate cancer (PCa) soft-tissue lesions. To meet the clinical need for a more cost-effective alternative, the PSMA-I&T-based tracer concept was adapted to Tc-labeling chemistry. Two PSMA-I&T-derived inhibitors with all-L-serine- (MAS) and all-D-serine- (mas) chelating moieties were evaluated in parallel, and a kit procedure for routine Tc labeling was developed.

Methods: PSMA affinities (IC) and internalization kinetics of Tc-MAS-y-nal-k(Sub-KuE) and Tc-mas-y-nal-k(Sub-KuE) (Tc-PSMA-I&S for imaging and surgery) were determined using LNCaP cells and (I-BA)KuE as a radioligand and reference standard. In vivo metabolite analyses and biodistribution studies were performed using CD-1 nu/nu and LNCaP tumor-bearing CB-17 severe combined immunodeficiency mice. The pharmacokinetics of Tc-PSMA-I&S in humans were investigated in a patient with advanced metastatic PCa via sequential planar whole-body SPECT imaging at 1, 3, 5, and 21 h after injection. Additionally, preoperative SPECT/CT (12 h after injection) and Tc-PSMA-I&S-supported RGS (16 h after injection) were performed in 1 PCa patient with proven iliac and inguinal lymph node metastases.

Results: A robust and reliable kit-labeling procedure was established, allowing the preparation of Tc-MAS-y-nal-k(Sub-KuE) and Tc-PSMA-I&S in consistently high radiochemical yield and purity (≥98%, n > 50 preparations). Because of its improved internalization efficiency and superior in vivo stability, Tc-PSMA-I&S was selected for further in vivo evaluation. Compared with In-PSMA-I&T, Tc-PSMA-I&S showed delayed clearance kinetics but identical uptake in PSMA-positive tissues in the LNCaP xenograft model (1 h after injection). In exemplary PCa patients, a relatively slow whole-body clearance of Tc-PSMA-I&S was observed due to high plasma protein binding (94%) of the tracer. This, however, promoted efficient tracer uptake in PCa lesions over time and led to steadily increasing lesion-to-background ratios up to 21 h after injection. Preoperative SPECT/CT showed a high Tc-PSMA-I&S uptake in all suspect lesions identified in previous Ga-HBED-CC-Ahx-KuE (Ga-HBED-CC-PSMA) PET/CT, allowing for their successful intraoperative detection and resection during first-in-human RGS.

Conclusion: Because of a straightforward and reliable kit production, Tc-PSMA-I&S represents a cost-effective, readily available alternative to In-PSMA-I&T. Initial patient data indicate its comparable or even superior performance as a probe for PSMA-targeted RGS and also hint toward the unexpected potential of Tc-PSMA-I&S as a SPECT imaging agent.
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http://dx.doi.org/10.2967/jnumed.116.178939DOI Listing
February 2017
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