Development and evaluation of deuterated [F]JHU94620 isotopologues for the non-invasive assessment of the cannabinoid type 2 receptor in brain.

Background: The cannabinoid type 2 receptors (CB2R) represent a target of increasing importance in neuroimaging due to its upregulation under various neuropathological conditions. Previous evaluation of [F]JHU94620 for the non-invasive assessment of the CB2R availability by positron emission tomography (PET) revealed favourable binding properties and brain uptake, however rapid metabolism, and generation of brain-penetrating radiometabolites have been its main limitations. To reduce the bias of CB2R quantification by blood-brain barrier (BBB)-penetrating radiometabolites, we aimed to improve the metabolic stability by developing -d and -d deuterated isotopologues of [F]JHU94620.

Selective PET imaging of CXCR4 using the AlF-labeled antagonist LY2510924.

Background: [Ga]PentixaFor detects C-X-C chemokine receptor type 4 (CXCR4) overexpression in various malignancies, such as multiple myeloma and non-Hodgkin lymphomas, as well as in endocrine and inflammatory disorders. This study aimed to develop an AlF-labeled radiotracer derived from LY2510924 for CXCR4-targeted imaging, leveraging the physical and logistical advantages of fluorine-18.

Methods: We designed a CXCR4-specific radioprobe, [F]AlF-NOTA-SC, based on LY2510924 by incorporating a triglutamate linker and NOTA chelator to enable AlF-labeling.

Translational Preclinical PET Imaging and Metabolic Evaluation of a New Cannabinoid 2 Receptor (CBR) Radioligand, ()--(3-(2-(2-[F]Fluoroethoxy)ethyl)-4,5-dimethylthiazol-2(3)-ylidene)-2,2,3,3-tetramethylcyclopropane-1-carboxamide.

We have previously developed seven fluorinated analogues of A-836339 as new PET tracers for cannabinoid type 2 receptor (CBR) imaging, among which ()--(3-(2-(2-[F]fluoroethoxy)ethyl)-4,5-dimethylthiazol-2(3)-ylidene)-2,2,3,3-tetramethylcyclopropane-1-carboxamide ([F]FC0324) displayed high affinity and selectivity for CBR in healthy rats. In the present study, we have further evaluated the imaging and metabolic properties of [F]FC0324 in a rat model of human CBR overexpression in the brain (AAV-CB) and in non-human primates (NHPs). Autoradiography with AAV-CB rat brain sections exhibited a signal of [F]FC0324 8-fold higher in the ipsilateral region than in the contralateral region.

HDAC6 inhibitors sensitize resistant t(11;14) multiple myeloma cells to a combination of bortezomib and BH3 mimetics.

Not available.

Clinical impact of using [F]AlF-NOTA-octreotide PET/CT instead of [Ga]Ga-DOTA-SSA PET/CT: Secondary endpoint analysis of a multicenter, prospective trial.

[F]AlF-NOTA-octreotide ([F]AlF-OC) is a promising alternative for [Ga]Ga-DOTA-somatostatin analogs (SSAs) in positron emission tomography (PET) imaging of the somatostatin receptor (SSTR). Our aim is to assess changes in TNM staging and differences in patient management between [F]AlF-OC PET/CT and [Ga]Ga-DOTA-SSA PET/CT in the work-up of neuroendocrine tumor (NET) patients. Patients who underwent both [F]AlF-OC and [Ga]Ga-DOTA-TATE or [Ga]Ga-DOTA-NOC PET/CT in our multicenter study (Pauwels et al.

Second generation AlF-labeled D-amino acid peptide for CXCR4 targeted molecular imaging.

Background: The C-X-C chemokine receptor type 4 (CXCR4) is overexpressed in many cancers, e.g. multiple myeloma and acute leukemia, yet solely [Ga]PentixaFor is used for clinical PET imaging.

Highlight selection of radiochemistry and radiopharmacy developments by editorial board.

Background: The Editorial Board of EJNMMI Radiopharmacy and Chemistry releases a biannual highlight commentary to update the readership on trends in the field of radiopharmaceutical development.

Main Body: This selection of highlights provides commentary on 21 different topics selected by each coauthoring Editorial Board member addressing a variety of aspects ranging from novel radiochemistry to first-in-human application of novel radiopharmaceuticals.

Conclusion: Trends in radiochemistry and radiopharmacy are highlighted.

Synthesis, Structure-Activity Relationships, Radiofluorination, and Biological Evaluation of [F]RM365, a Novel Radioligand for Imaging the Human Cannabinoid Receptor Type 2 (CB2R) in the Brain with PET.

The development of cannabinoid receptor type 2 (CB2R) PET radioligands has been intensively explored due to the pronounced CB2R upregulation under various pathological conditions. Herein, we report on the synthesis of a series of CB2R affine fluorinated indole-2-carboxamide ligands. Compound RM365 was selected for PET radiotracer development due to its high CB2R affinity ( = 2.

Radiopharmaceuticals for Cancer Imaging and Therapy.

Nuclear medicine has emerged as a pivotal player in cancer patient care, revolutionizing the way cancer is detected, diagnosed, monitored, and treated [...

Prospective comparison of [F]AlF-NOTA-octreotide PET/MRI to [Ga]Ga-DOTATATE PET/CT in neuroendocrine tumor patients.

Background: Fluorine-18-labeled SSAs have the potential to become the next-generation tracer in SSTR-imaging in neuroendocrine tumor (NET) patients given their logistical advantages over the current gold standard gallium-68-labeled SSAs. In particular, [F]AlF-OC has already shown excellent clinical performance. We demonstrated in our previous report from our prospective multicenter trial that [F]AlF-OC PET/CT outperforms [Ga]Ga-DOTA-SSA, but histological confirmation was lacking due to ethical and practical reasons.

Preclinical Evaluation of Novel PET Probes for Dementia.

The development of novel PET imaging agents that selectively bind specific dementia-related targets can contribute significantly to accurate, differential and early diagnosis of dementia causing diseases and support the development of therapeutic agents. Consequently, in recent years there has been a growing body of literature describing the development and evaluation of potential new promising PET tracers for dementia. This review article provides a comprehensive overview of novel dementia PET probes under development, classified by their target, and pinpoints their preclinical evaluation pathway, typically involving in silico, in vitro and ex/in vivo evaluation.

Direct comparison of [F]AlF-NOTA-JR11 and [F]AlF-NOTA-octreotide for PET imaging of neuroendocrine tumors: Antagonist versus agonist.

Background: [F]AlF-NOTA-octreotide is an F-labeled somatostatin analogue which is a good clinical alternative for Ga-labeled somatostatin analogues. However, radiolabeled somatostatin receptor (SSTR) antagonists might outperform agonists regarding imaging sensitivity of neuroendocrine tumors (NETs). No direct comparison between the antagonist [F]AlF-NOTA-JR11 and the agonist [F]AlF-NOTA-octreotide as SSTR PET probes is available.

Radiosynthesis and preclinical evaluation of [C]SNX-ab as an Hsp90α,β isoform-selective PET probe for in vivo brain and tumour imaging.

Background: The molecular chaperone, Hsp90, is a key player in the protein quality control system that maintains homeostasis under cellular stress conditions. It is a homodimer with ATP-dependent activity, and is a prominent member of the chaperone machinery that stabilizes, matures and (re)folds an extensive list of client proteins. Hsp90 occurs as four isoforms, cytosolic Hsp90α and Hsp90β, mitochondrial TRAP1 and Grp94 present in the endoplasmic reticulum.

F-JK-PSMA-7 PET/CT for staging intermediate- or high-risk prostate cancer patients before radical prostatectomy: a pilot study.

Background: Positron emission tomography/computed tomography (PET/CT) using radiotracers that bind to the prostate-specific membrane antigen (PSMA) is mainly used in biochemical recurring prostate cancer. The aim of our study was to assess the usefulness of F-JK-PSMA-7 PET/CT for local and nodal staging in patients with intermediate- and high-risk prostate cancer (PCa) prior to radical prostatectomy, as compared to conventional imaging techniques.

Methods: We enrolled a total of 10 patients with intermediate- and high-risk PCa diagnosed by multiparametric-MRI followed by systematic and targeted biopsies, eligible for radical prostatectomy with extended lymph node dissection.

Utilizing PET and MALDI Imaging for Discovery of a Targeted Probe for Brain Endocannabinoid /-Hydrolase Domain 6 (ABHD6).

Multimodal imaging provides rich biological information, which can be exploited to study drug activity, disease associated phenotypes, and pharmacological responses. Here we show discovery and validation of a new probe targeting the endocannabinoid α/β-hydrolase domain 6 (ABHD6) enzyme by utilizing positron emission tomography (PET) and matrix-assisted laser desorption/ionization (MALDI) imaging. [F]JZP-MA-11 as the first PET ligand for imaging of the ABHD6 is reported and specific uptake in ABHD6-rich peripheral tissues and major brain regions was demonstrated using PET.

[F] MFBG PET imaging: biodistribution, pharmacokinetics, and comparison with [I] MIBG in neural crest tumour patients.

Purpose: Despite its limitations, [I]MIBG scintigraphy has been the standard for human norepinephrine transporter (hNET) imaging for several decades. Recently, [F]MFBG has emerged as a promising PET alternative. This prospective trial aimed to evaluate safety, biodistribution, tumour lesion pharmacokinetics, and lesion targeting of [F]MFBG and perform a head-to-head comparison with [I]MIBG in neural crest tumour patients.

In Vivo Detection of Neurofibrillary Tangles by F-MK-6240 PET/MR in Patients With Ischemic Stroke.

Background And Objectives: The risk of developing Alzheimer disease is increased after stroke, and this association may not solely be driven by traditional vascular risk factors. Neuronal death leads to the release of tau proteins, which can become dephosphorylated, rephosphorylated, or hyperphosphorylated in the setting of ischemia, possibly leading to formation of neurofibrillary tangles (NFT). Therefore, a potential synergistic effect between development of tauopathy and cerebrovascular lesion burden may contribute to cognitive decline after stroke.

F-AlF-NOTA-Octreotide Outperforms Ga-DOTATATE/NOC PET in Neuroendocrine Tumor Patients: Results from a Prospective, Multicenter Study.

F-labeled somatostatin analogs (SSAs) could represent a valid alternative to the current gold standard, Ga-labeled SSAs, for somatostatin receptor imaging in patients with neuroendocrine tumors (NETs), given their logistic advantages. Recently, F-AlF-NOTA-octreotide (F-AlF-OC) has emerged as a promising candidate, but a thorough comparison with Ga-DOTA-SSA in large patient groups is needed. This prospective, multicenter trial aims to demonstrate noninferiority of F-AlF-OC compared with Ga-DOTA-SSA PET in NET patients (ClinicalTrials.

Towards updated understanding of brain metastasis.

Brain metastasis (BM) is a common complication in cancer patients with advanced disease and attributes to treatment failure and final mortality. Currently there are several therapeutic options available; however these are only suitable for limited subpopulation: surgical resection or radiosurgery for cases with a limited number of lesions, targeted therapies for approximately 18% of patients, and immune checkpoint inhibitors with a response rate of 20-30%. Thus, there is a pressing need for development of novel diagnostic and therapeutic options.

Biodistribution and dosimetry in human healthy volunteers of the PET radioligands [C]CHDI-00485180-R and [C]CHDI-00485626, designed for quantification of cerebral aggregated mutant huntingtin.

Purpose: Huntington's disease is caused by a trinucleotide expansion in the HTT gene, which leads to aggregation of mutant huntingtin (mHTT) protein in the brain and neurotoxicity. Direct in vivo measurement of mHTT aggregates in human brain parenchyma is not yet possible. In this first-in-human study, we investigated biodistribution and dosimetry in healthy volunteers of [C]CHDI-00485180-R ([C]CHDI-180R) and [C]CHDI-00485626 ([C]CHDI-626), two tracers designed for PET imaging of aggregated mHTT in the brain that have been validated in preclinical models.

3p-C-NETA: A versatile and effective chelator for development of AlF-labeled and therapeutic radiopharmaceuticals.

: Radiolabeled somatostatin analogues ( [Ga]Ga-DOTATATE and [Lu]Lu-DOTATATE) have been used to diagnose, monitor, and treat neuroendocrine tumour (NET) patients with great success. [F]AlF-NOTA-octreotide, a promising F-labeled somatostatin analogue and potential alternative for Ga-DOTA-peptides, is under clinical evaluation. However, ideally, the same precursor (combination of chelator-linker-vector) can be used for production of both diagnostic and therapeutic radiopharmaceuticals with very similar ( AlF-method in combination with therapeutic radiometals Bi/Lu) or identical ( complementary Tb-radionuclides) pharmacokinetic properties, allowing for accurate personalised dosimetry estimation and radionuclide therapy of NET patients.

Structure-Based Design, Optimization, and Development of [F]LU13: A Novel Radioligand for Cannabinoid Receptor Type 2 Imaging in the Brain with PET.

The cannabinoid receptor type 2 (CB2R) is an attractive target for the diagnosis and therapy of neurodegenerative diseases and cancer. In this study, we aimed at the development of a novel F-labeled radioligand starting from the structure of the known naphthyrid-2-one CB2R ligands. Compound () was identified with the highest binding affinity and selectivity versus CB1R (CB2R = 0.