Automatic Production and Preliminary PET Imaging of a New Imaging Agent [18F]AlF-FAPT

BackgroundFibroblast activating protein (FAP) has become an important target for cancer diagnostic imaging and targeted radiotherapy. In particular, [18F]FAPI-42 has been successfully applied to positron emission tomography (PET) imaging of various tumors. However, it exhibits high hepatobiliary metabolism and is thus not conducive to abdominal tumor imaging. This study reports a novel 18F-labeled FAP inhibitor, [18F]AlF-FAPT, a better FAPI imaging agent than [18F]FAPI-42.Materials and MethodsThe precursor of [18F]AlF-FAPT (NOTA-FAPT) was designed and synthesized using the standard FMOC solid phase synthesis method. [18F]AlF-FAPT was subsequently synthesized and radiolabeled with 18F using the AllInOne synthesis module. Dynamic MicroPET and biodistribution studies of [18F]AlF-FAPT were then conducted in xenograft tumor mouse models to determine its suitability.ResultsThe precursors NOTA-FAPT were obtained with a chemical purity of > 95%. [18F]AlF-FAPT was synthesized automatically using the cassette-based module AllInOne within 40 min. The non-decay corrected radiochemical yield was 25.0 ± 5.3% (n=3). In vivo imaging and biodistribution studies further demonstrated that compared with [18F]-FAPI-42, [18F]AlF-FAPT had a lower hepatobiliary uptake than [18F]FAPI-42, which was advantageous for imaging abdominal tumors.Conclusion[18F]AlF-FAPT can be synthesized automatically using a one-step method of aluminum fluoride. Collectively, [18F]AlF-FAPT is a better FAPI imaging agent than [18F]FAPI-42. This study proves the feasibility of using [18F]AlF-FAPT as a new radioactive tracer for PET imaging.

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68Ga-labeled HBED-CC Variant of uPAR Targeting Peptide AE105 Compared with 68Ga-NODAGA-AE105

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520618666180316152618 ◽

2019 ◽

Vol 18 (9) ◽

pp. 1289-1294 ◽

Cited By ~ 1

Author(s):

Kusum Vats ◽

Rohit Sharma ◽

Haladhar D. Sarma ◽

Drishty Satpati ◽

Ashutosh Dash

Keyword(s):

Solid Phase ◽

Evaluation Studies ◽

Radiochemical Yield ◽

In Vivo Evaluation ◽

Peptide Conjugates ◽

Biodistribution Studies ◽

Target Organs ◽

U87mg Tumor

Aims: The urokinase Plasminogen Activator Receptors (uPAR) over-expressed on tumor cells and their invasive microenvironment are clinically significant molecular targets for cancer research. uPARexpressing cancerous lesions can be suitably identified and their progression can be monitored with radiolabeled uPAR targeted imaging probes. Hence this study aimed at preparing and evaluating two 68Ga-labeled AE105 peptide conjugates, 68Ga-NODAGA-AE105 and 68Ga-HBED-CC-AE105 as uPAR PET-probes. Method: The peptide conjugates, HBED-CC-AE105-NH2 and NODAGA-AE105-NH2 were manually synthesized by standard Fmoc solid phase strategy and subsequently radiolabeled with 68Ga eluted from a commercial 68Ge/68Ga generator. In vitro cell studies for the two radiotracers were performed with uPAR positive U87MG cells. Biodistribution studies were carried out in mouse xenografts with the subcutaneously induced U87MG tumor. Results: The two radiotracers, 68Ga-NODAGA-AE105 and 68Ga-HBED-CC-AE105 that were prepared in >95% radiochemical yield and >96% radiochemical purity, exhibited excellent in vitro stability. In vivo evaluation studies revealed higher uptake of 68Ga-HBED-CC-AE105 in U87MG tumor as compared to 68Ga-NODAGAAE105; however, increased lipophilicity of 68Ga-HBED-CC-AE105 resulted in slower clearance from blood and other non-target organs. The uPAR specificity of the two radiotracers was ascertained by significant (p<0.05) reduction in the tumor uptake with a co-injected blocking dose of unlabeled AE-105 peptide. Conclusion: Amongst the two radiotracers studied, the neutral 68Ga-NODAGA-AE105 with more hydrophilic chelator exhibited faster clearance from non-target organs. The conjugation of HBED-CC chelator (less hydrophilic) resulted in negatively charged 68Ga-HBED-CC-AE105 which was observed to have high retention in blood that decreased target to non-target ratios.

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Improved synthesis of SV2A targeting radiotracer [11C]UCB-J

EJNMMI Radiopharmacy and Chemistry ◽

10.1186/s41181-019-0080-5 ◽

2019 ◽

Vol 4 (1) ◽

Cited By ~ 2

Author(s):

Johanna Rokka ◽

Eva Schlein ◽

Jonas Eriksson

Keyword(s):

Methyl Iodide ◽

Water Solution ◽

Synthesis Method ◽

Radiochemical Yield ◽

Preparative Hplc ◽

Step Method ◽

Synaptic Density ◽

Excellent Starting Point ◽

Starting Point

Abstract Introduction [11C]UCB-J is a tracer developed for PET (positron emission tomography) that has high affinity towards synaptic vesicle glycoprotein 2A (SV2A), a protein believed to participate in the regulation of neurotransmitter release in neurons and endocrine cells. The localisation of SV2A in the synaptic terminals makes it a viable target for in vivo imaging of synaptic density in the brain. Several SV2A targeting compounds have been evaluated as PET tracers, including [11C]UCB-J, with the aim to facilitate studies of synaptic density in neurological diseases. The original two-step synthesis method failed in our hands to produce sufficient amounts of [11C]UCB-J, but served as an excellent starting point for further optimizations towards a high yielding and simplified one-step method. [11C]Methyl iodide was trapped in a clear THF-water solution containing the trifluoroborate substituted precursor, potassium carbonate and palladium complex. The resulting reaction mixture was heated at 70 °C for 4 min to produce [11C]UCB-J. Results After semi-preparative HPLC purification and reformulation in 10% ethanol/phosphate buffered saline, the product was obtained in 39 ± 5% radiochemical yield based on [11C]methyl iodide, corresponding to 1.8 ± 0.5 GBq at EOS. The radiochemical purity was > 99% and the molar activity was 390 ± 180 GBq/μmol at EOS. The product solution contained < 2 ppb palladium. Conclusions A robust and high yielding production method has been developed for [11C]UCB-J, suitable for both preclinical and clinical PET applications.

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Synthesis and in vivo evaluation of [18F]N-(2-benzofuranylmethyl)-N′-[4-(2-fluoroethoxy)benzyl]piperazine, a novel σ1 receptor PET imaging agent

Bioorganic & Medicinal Chemistry Letters ◽

10.1016/j.bmcl.2011.09.028 ◽

2011 ◽

Vol 21 (22) ◽

pp. 6820-6823 ◽

Cited By ~ 10

Author(s):

Iman A. Moussa ◽

Samuel D. Banister ◽

Nicolas Giboureau ◽

Steven R. Meikle ◽

Michael Kassiou

Keyword(s):

Pet Imaging ◽

Imaging Agent ◽

In Vivo Evaluation ◽

Σ1 Receptor

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Radiosynthesis and in vivo evaluation of [ 11 C]MOV as a PET imaging agent for COX-2

Bioorganic & Medicinal Chemistry Letters ◽

10.1016/j.bmcl.2018.06.015 ◽

2018 ◽

Vol 28 (14) ◽

pp. 2432-2435 ◽

Cited By ~ 4

Author(s):

Jaya Prabhakaran ◽

Mark Underwood ◽

Francesca Zanderigo ◽

Norman R. Simpson ◽

Anna R. Cooper ◽

...

Keyword(s):

Pet Imaging ◽

Imaging Agent ◽

In Vivo Evaluation ◽

Cox 2

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A PET imaging agent with fast kinetics: synthesis and in vivo evaluation of the serotonin transporter ligand [11C]2-[2-dimethylaminomethylphenylthio)]-5-fluorophenylamine ([11C]AFA)

Nuclear Medicine and Biology ◽

10.1016/j.nucmedbio.2004.03.010 ◽

2004 ◽

Vol 31 (6) ◽

pp. 727-738 ◽

Cited By ~ 16

Author(s):

Yiyun Huang ◽

Raj Narendran ◽

Sung-A Bae ◽

David Erritzoe ◽

Ningning Guo ◽

...

Keyword(s):

Serotonin Transporter ◽

Pet Imaging ◽

Imaging Agent ◽

In Vivo Evaluation ◽

Fast Kinetics

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64Cu-galectin-3-specific peptide as an in vivo PET imaging agent

Nuclear Medicine and Biology ◽

10.1016/j.nucmedbio.2010.04.054 ◽

2010 ◽

Vol 37 (6) ◽

pp. 725

Author(s):

Susan L. Deutscher ◽

Senthil R. Kumar ◽

Thomas P. Quinn

Keyword(s):

Pet Imaging ◽

Imaging Agent ◽

Galectin 3 ◽

Specific Peptide

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Strain-Promoted Azide-Alkyne Cycloaddition-Based PSMA-Targeting Ligands For Multimodal Intraoperative Tumor Detection of Prostate Cancer

10.21203/rs.3.rs-925760/v1 ◽

2021 ◽

Author(s):

Yvonne H.W. Derks ◽

Mark Rijpkema ◽

Helene I.V. Amatdjais-Groenen ◽

Cato Loeff ◽

Kim E. de Roode ◽

...

Keyword(s):

Prostate Cancer ◽

Fluorescence Imaging ◽

Tumor Targeting ◽

Solid Phase ◽

Biodistribution Studies ◽

Specific Tumor ◽

Multiple Imaging ◽

Specific Accumulation ◽

Modular Platform

Abstract Purpose: Strain-promoted azide-alkyne cycloaddition (SPAAC) is a straightforward and multipurpose conjugation strategy. Use of SPAAC to link different functional elements to prostate specific membrane antigen (PSMA) ligands would facilitate the development of a modular platform for PSMA-targeted imaging and therapy of prostate cancer (PCa). As a first proof-of-concept for the SPAAC chemistry platform we synthesized and characterized four dual-labeled PSMA ligands for intraoperative radiodetection and fluorescence imaging of PCa. Methods: Ligands were synthesized using solid phase chemistry and contained a chelator for 111In or 99mTc labeling. The fluorophore IRDye800CW was conjugated using SPAAC chemistry or conventional N-hydroxysuccinimide (NHS)-ester coupling. LogD values were measured and PSMA-specificity of these ligands was determined in LS174T-PSMA cells. Tumor targeting was evaluated in BALB/c nude mice with subcutaneous LS174T-PSMA and LS174T wildtype tumors using µSPECT/CT imaging, fluorescence imaging, and biodistribution studies. Results: SPAAC chemistry increased lipophilicity of the ligands (range LogD: -2.4 to -4.4). In vivo, SPAAC chemistry ligands showed high and specific accumulation in s.c. LS174T-PSMA tumors up to 24 hours after injection, enabling clear visualization using µSPECT/CT and fluorescence imaging. Overall, no significant differences between the SPAAC chemistry ligands and their NHS-based counterparts were found (2 h p.i., p > 0.05), while 111In-labeled ligands outperformed the 99mTc ligands. Conclusion: Here we demonstrate that our newly developed SPAAC-based PSMA ligands show high PSMA-specific tumor targeting. Use of click-chemistry in PSMA ligand development opens up the opportunity for fast, efficient and versatile conjugations of multiple imaging moieties and/or drugs.

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Design of a multivalent bifunctional chelator for diagnostic64Cu PET imaging in Alzheimer’s disease

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2014058117 ◽

2020 ◽

Vol 117 (49) ◽

pp. 30928-30933

Author(s):

Hong-Jun Cho ◽

Truc T. Huynh ◽

Buck E. Rogers ◽

Liviu M. Mirica

Keyword(s):

Pet Imaging ◽

Imaging Agent ◽

Brain Uptake ◽

Wild Type ◽

Bifunctional Chelator ◽

Positron Emission ◽

Specific Affinity ◽

Amyloid Aβ ◽

5Xfad Mice

Herein, we report a64Cu positron emission tomography (PET) imaging agent that shows appreciable in vivo brain uptake and exhibits high specific affinity for beta-amyloid (Aβ) aggregates, leading to the successful PET imaging of amyloid plaques in the brains of 5xFAD mice versus those of wild-type mice. The employed approach uses a bifunctional chelator with two Aβ-interacting fragments that dramatically improves the Aβ-binding affinity and lipophilicity for favorable blood–brain barrier penetration, while the use of optimized-length spacers between the Cu-chelating group and the Aβ-interacting fragments further improves the in vivo Aβ-binding specificity and brain uptake of the corresponding64Cu PET imaging agent.

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