Second generation Al18F-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 [68Ga]PentixaFor is used for clinical PET imaging. The aim of this study was to develop and assess a second generation Al18F-labeled D-amino acid peptide based on the viral macrophage inflammatory protein II for CXCR4 targeted molecular imaging. METHODS: We designed a library of monomer and multimer constructs and evaluated their binding affinity for human and mouse CXCR4. Based on these results, we selected the best vector molecule for development of an Al18F-labeled ligand, [18F]AlF-NOTA-2xDV1(c11sc12s), which was further evaluated in a cell-based binding assay to assess its binding properties and specificity for CXCR4. Next, pharmacokinetics and tumor uptake of [18F]AlF-NOTA-2xDV1(c11sc12s) were evaluated in naïve mice and mice with xenografts derived from U87.CXCR4 cells. Finally, we performed an imaging study in a non-human primate to assess the in vivo distribution of this novel radioligand in a species closely related to humans. RESULTS: The lead ligand AlF-NOTA-2xDV1(c11sc12s) showed six-fold higher affinity for human CXCR4 compared to Ga-Pentixafor. The corresponding radiotracer was obtained in a good radiochemical yield of 40.1 ± 13.5 % (n = 4) and apparent molar activity of 20.4 ± 3.3 MBq/nmol (n = 4) after optimization. In U87.CD4.CXCR4 cell binding assays, the total bound fraction of [18F]AlF-NOTA-(2×)DV1(c11sc12s) was 32.4 ± 1.8 %. This fraction could be reduced by 82.5 % in the presence of 75 µM AMD3100. In naïve mice, [18F]AlF-NOTA-2xDV1(c11sc12s) accumulated in organs expressing mouse CXCR4, e.g. the liver (SUVmean (mean standardized uptake value) 75 min p.i. 11.7 ± 0.6), which was blockable by co-injecting AMD3100 (5 mg/kg). In U87.CXCR4 xenografted tumor mice, the tumor uptake of [18F]AlF-NOTA-2xDV1(c11sc12s) remained low (SUVmean 0.5 ± 0.1), but was reduced by co-administration of AMD3100. Surprisingly, [18F]AlF-NOTA-2xDV1(c11sc12s) exhibited a similar biodistribution in a non-human primate as in mice indicating off-target binding of [18F]AlF-NOTA-2xDV1(c11sc12s) in liver tissue. We confirmed that [18F]AlF-NOTA-2xDV1(c11sc12s) is taken up by hepatocytes using in vitro studies and that the uptake can be blocked with AMD3100 and rifampicin, a potent organic anion-transporting-polypeptide (OATP)1B1 and OATP1B3 inhibitor. CONCLUSION: The second generation D-peptide AlF-NOTA-2xDV1(c11sc12s) showed high affinity for human CXCR4 and the corresponding radiotracer was produced in good radiochemical yields. However, [18F]AlF-NOTA-2xDV1(c11sc12s) is not specific for CXCR4 and is also a substrate for OATP1B1 and/or OATP1B3, known to mediate hepatic uptake. Therefore, D-amino acid peptides, based on the viral macrophage inflammatory protein II, are not the prefered vector molecule for the development of CXCR4 targeting molecular imaging tools.

Synthesis, Structure-Activity Relationships, Radiofluorination, and Biological Evaluation of [18F]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 (Ki = 2.1 nM) and selectivity over CB1R (factor > 300). Preliminary in vitro evaluation of [18F]RM365 indicated species differences in the binding to CB2R (KD of 2.32 nM for the hCB2R vs KD > 10,000 nM for the rCB2R). Metabolism studies in mice revealed a high in vivo stability of [18F]RM365. PET imaging in a rat model of local hCB2R(D80N) overexpression in the brain demonstrates the ability of [18F]RM365 to reach and selectively label the hCB2R(D80N) with a high signal-to-background ratio. Thus, [18F]RM365 is a very promising PET radioligand for the imaging of upregulated hCB2R expression under pathological conditions.

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. Hot topics cover the entire scope of EJNMMI Radiopharmacy and Chemistry, demonstrating the progress in the research field in many aspects.

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 [18F]AlF-NOTA-octreotide PET/MRI to [68Ga]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, [18F]AlF-OC has already shown excellent clinical performance. We demonstrated in our previous report from our prospective multicenter trial that [18F]AlF-OC PET/CT outperforms [68Ga]Ga-DOTA-SSA, but histological confirmation was lacking due to ethical and practical reasons. In this second arm, we therefore aimed to provide evidence that the vast majority of [18F]AlF-OC PET lesions are in fact true NET lesions by analyzing their MR characteristics on simultaneously acquired MRI. We had a special interest in lesions solely detected by [18F]AlF-OC ("incremental lesions"). METHODS: Ten patients with a histologically confirmed neuroendocrine tumor (NET) and a standard-of-care [68Ga]Ga-DOTATATE PET/CT, performed within 3 months, were prospectively included. Patients underwent a whole-body PET/MRI (TOF, 3 T, GE Signa), 2 hours after IV injection of 4 MBq/kg [18F]AlF-OC. Positive PET lesions were evaluated for a corresponding lesion on MRI. The diagnostic performance of both PET tracers was evaluated by determining the detection ratio (DR) for each scan and the differential detection ratio (DDR) per patient. RESULTS: In total, 195 unique lesions were detected: 167 with [68Ga]Ga-DOTATATE and 193 with [18F]AlF-OC. The DR for [18F]AlF-OC was 99.1% versus 91.4% for [68Ga]Ga-DOTATATE, significant for non-inferiority testing (p = 0.0001). Out of these 193 [18F]AlF-OC lesions, 96.2% were confirmed by MRI to be NET lesions. Thirty-three incremental lesions were identified by [18F]AlF-OC, of which 91% were confirmed by MRI and considered true positives. CONCLUSION: The DR of [18F]AlF-OC was numerically higher and non-inferior to the DR of [68Ga]Ga-DOTATATE. [18F]AlF-OC lesions and especially incremental lesions were confirmed as true positives by MRI in more than 90% of lesions. Taken together, these data further validate [18F]AlF-OC as a new alternative for SSTR PET in clinical practice. Trial registration ClinicalTrials.gov: NCT04552847. Registered 17 September 2020, https://beta. CLINICALTRIALS: gov/study/NCT04552847.

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. Specific target-associated challenges and pitfalls, requiring extensive and well-designed preclinical experimental evaluation assays to enable successful clinical translation and avoid shortcomings observed for previously developed 'well-established' dementia PET tracers are highlighted in this review.

Direct comparison of [18F]AlF-NOTA-JR11 and [18F]AlF-NOTA-octreotide for PET imaging of neuroendocrine tumors: Antagonist versus agonist.

BACKGROUND: [18F]AlF-NOTA-octreotide is an 18F-labeled somatostatin analogue which is a good clinical alternative for 68Ga-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 [18F]AlF-NOTA-JR11 and the agonist [18F]AlF-NOTA-octreotide as SSTR PET probes is available. Herein, we present the radiosynthesis of [18F]AlF-NOTA-JR11 and compare its NETs imaging properties directly with the established agonist radioligand [18F]AlF-NOTA-octreotide preclinically. METHODS: [18F]AlF-NOTA-JR11 was synthesized in an automated synthesis module. The in vitro binding characteristics (IC50) of [natF]AlF-NOTA-JR11 and [natF]AlF-NOTA-octreotide were evaluated and the in vitro stability of [18F]AlF-NOTA-JR11 was determined in human serum. In vitro cell binding and internalization was performed with [18F]AlF-NOTA-JR11 and [18F]AlF-NOTA-octreotide using SSTR2 expressing cells and the pharmacokinetics were evaluated using µPET/CT in mice bearing BON1.SSTR2 tumor xenografts. RESULTS: Excellent binding affinity for SSTR2 was found for [natF]AlF-NOTA-octreotide (IC50 of 25.7 ± 7.9 nM). However, the IC50 value for [natF]AlF-NOTA-JR11 (290.6 ± 71 nM) was 11-fold higher compared to [natF]AlF-NOTA-octreotide, indicating lower affinity for SSTR2. [18F]AlF-NOTA-JR11 was obtained in a good RCY (50 ± 6 %) but with moderate RCP of 94 ± 1 %. [18F]AlF-NOTA-JR11 demonstrated excellent stability in human serum (>95 % after 240 min). 2.7-fold higher cell binding was observed for [18F]AlF-NOTA-JR11 as compared to [18F]AlF-NOTA-octreotide after 60 min. µPET/CT images demonstrated comparable pharmacokinetics and tumor uptake between [18F]AlF-NOTA-JR11 (SUVmax: 3.7 ± 0.8) and [18F]AlF-NOTA-octreotide (SUVmax: 3.6 ± 0.4). CONCLUSIONS: [18F]AlF-NOTA-JR11 was obtained in good RCY, albeit with a moderate RCP. The cell binding study showed significant higher binding of [18F]AlF-NOTA-JR11 compared to [18F]AlF-NOTA-octreotide, despite the higher IC50 value of AlF-NOTA-JR11. However, pharmacokinetics and in vivo tumor uptake was comparable for both radiotracers. Novel Al18F-labeled derivatives of JR11 with higher SSTR2 affinity should be developed for increased tumor uptake and NET imaging sensitivity.

18F-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 18F-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. Clinical team was blind to the results of the pre-surgery 18F-JK-PSMA-7 PET/CT at times of clinical decision and surgery. One month post-surgery, 18F-JK-PSMA-7 PET/CT was repeated and the results of both scans were unblinded. A third 18F-JK-PSMA-7 PET/CT could be acquired at a later time point depending on PSA progression. RESULTS: All pre-surgery 18F-JK-PSMA-7 PET/CT was positive in the prostatic region, while MRI was negative in the prostate in one patient. We also detected positive pelvic lymph nodes in two patients (one high-risk, one intermediate-risk PCa) on pre-surgery and post-surgery 18F-JK-PSMA-7 PET/CT. No positive pelvic lymph nodes were reported on pre-surgical CT and MRI. 18F-JK-PSMA-7 PET/CT detected bladder involvement in one patient and seminal vesicles involvement in two patients; this malignant extension was undetected by the conventional imaging techniques. SUVmax in prostate lesions had an average value of 11.51 (range 6.90-21.49). SUVmean in prostate lesions had an average value of 7.59 (range 5.26-14.02). CONCLUSION: This pilot study indicates that pre-surgery 18F-JK-PSMA-7 PET/CT provides valuable information in intermediate- and high-risk PCa, for surgery planning with curative intent.

Radiosynthesis and preclinical evaluation of [11C]SNX-ab as an Hsp90α,ß 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 Hsp90ß, mitochondrial TRAP1 and Grp94 present in the endoplasmic reticulum. An aberrant role of Hsp90 has been attributed to several cancers and neurodegenerative disorders. Consequently, Hsp90 has emerged as an attractive therapeutic target. However, pan-Hsp90 inhibition often leads to detrimental dose-limiting toxicities. Novel strategies for Hsp90-targeted therapy intend to avoid this by using isoform-specific Hsp90 inhibition. In this respect, the radiosynthesis of carbon-11 labeled SNX-ab was developed and [11C]SNX-ab was evaluated as a Hsp90α,ß isoform-selective PET probe, which could potentially allow to quantify in vivo Hsp90α,ß expression. RESULTS: [11C]SNX-ab was synthesized with excellent radiochemical yields of 45% and high radiochemical purity (> 98%). In vitro autoradiography studies on tissue slices of healthy mouse brain, mouse B16.F10 melanoma and U87 glioblastoma using homologous (SNX-ab, SNX-0723) and heterologous (Onalespib and PU-H71) Hsp90 inhibitors demonstrated only limited reduction of tracer binding, indicating that the binding of [11C]SNX-ab was not fully Hsp90-specific. Similarly, [11C]SNX-ab binding to U87 cells was not efficiently inhibited by Hsp90 inhibitors. Ex vivo biodistribution studies in healthy mice revealed limited brain exposure of [11C]SNX-ab and predominantly hepatobiliary clearance, which was confirmed by in vivo full-body dynamic µPET studies. CONCLUSION: Our results suggest that [11C]SNX-ab is not an ideal probe for in vivo visualization and quantification of Hsp90α/ß expression levels in tumour and brain. Future research in the development of next-generation Hsp90 isoform-selective PET tracers is warranted to dissect the role played by each isoform towards disease pathology and support the development of subtype-specific Hsp90 therapeutics.

Utilizing PET and MALDI Imaging for Discovery of a Targeted Probe for Brain Endocannabinoid α/ß-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/ß-hydrolase domain 6 (ABHD6) enzyme by utilizing positron emission tomography (PET) and matrix-assisted laser desorption/ionization (MALDI) imaging. [18F]JZP-MA-11 as the first PET ligand for in vivo imaging of the ABHD6 is reported and specific uptake in ABHD6-rich peripheral tissues and major brain regions was demonstrated using PET. A proof-of-concept study in nonhuman primate confirmed brain uptake. In vivo pharmacological response upon ABHD6 inhibition was observed by MALDI imaging. These synergistic imaging efforts used to identify biological information cannot be obtained by a single imaging modality and hold promise for improving the understanding of ABHD6-mediated endocannabinoid metabolism in peripheral and central nervous system disorders.

[18F] MFBG PET imaging: biodistribution, pharmacokinetics, and comparison with [123I] MIBG in neural crest tumour patients.

PURPOSE: Despite its limitations, [123I]MIBG scintigraphy has been the standard for human norepinephrine transporter (hNET) imaging for several decades. Recently, [18F]MFBG has emerged as a promising PET alternative. This prospective trial aimed to evaluate safety, biodistribution, tumour lesion pharmacokinetics, and lesion targeting of [18F]MFBG and perform a head-to-head comparison with [123I]MIBG in neural crest tumour patients. METHODS: Six neural crest tumour patients (4 phaeochromocytoma, 1 paraganglioma, 1 neuroblastoma) with a recent routine clinical [123I]MIBG scintigraphy (interval: - 37-75 days) were included. Adult patients (n = 5) underwent a 30-min dynamic PET, followed by 3 whole-body PET/CT scans at 60, 120, and 180 min after injection of 4 MBq/kg [18F]MFBG. One minor participant underwent a single whole-body PET/CT at 60 min after administration of 2 MBq/kg [18F]MFBG. Normal organ uptake (SUVmean) and lesion uptake (SUVmax; tumour-to-background ratio (TBR)) were measured. Regional distribution volumes (VT) were estimated using a Logan graphical analysis in up to 6 lesions per patient. A lesion-by-lesion analysis was performed to compare detection ratios (DR), i.e. fraction of detected lesions, between [18F]MFBG and [123I]MIBG. RESULTS: [18F]MFBG was safe and well tolerated. Its biodistribution was overall similar to that of [123I]MIBG, with prominent uptake in the salivary glands, liver, left ventricle wall and adrenals, and mainly urinary excretion. In the phaeochromocytoma subgroup, the median VT was 37.4 mL/cm3 (range: 18.0-144.8) with an excellent correlation between VT and SUVmean at all 3 time points (R2: 0.92-0.94). Mean lesion SUVmax and TBR at 1 h after injection were 19.3 ± 10.7 and 23.6 ± 8.4, respectively. All lesions detected with [123I]MIBG were also observed with [18F]MFBG. The mean DR with [123I]MIBG was significantly lower than with [18F]MFBG (61.0% ± 26.7% vs. 99.8% ± 0.5% at 1 h; p = 0.043). CONCLUSION: [18F]MFBG is a promising hNET imaging agent with favourable imaging characteristics and improved lesion targeting compared with [123I]MIBG scintigraphy. TRIAL REGISTRATION: Clinicaltrials.gov : NCT04258592 (Registered: 06 February 2020), EudraCT: 2019-003872-37A.

In Vivo Detection of Neurofibrillary Tangles by 18F-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. We explored the spatial and temporal distribution of NFT after ischemic stroke in vivo by using 18F-MK-6240 PET. METHODS: We included patients with a first ischemic stroke to undergo longitudinal 18F-MK-6240 PET/MR within 2-4 weeks and 6 months after stroke. For cross-sectional analyses, we also included age-matched healthy controls. We delineated 5 volumes of interest based on T2 FLAIR and T1 MR data: the ischemic lesion, 3 consecutive peri-ischemic areas, and the remaining ipsilesional hemisphere. We performed region-based voxel-wise partial volume correction on the PET data and calculated standardized uptake value ratios (SUVRs) with the cerebellum as the reference region. RESULTS: We did not quantify PET scans of patients within the first month after stroke (n = 17; median age 73 years [interquartile range {IQR}: 62-82 years]) because the signal intensity was influenced by blood-brain barrier breakdown hampering a reliable data analysis. At 6 months after the event (n = 13; median age 71 years [IQR: 60-79 years]), 18F-MK-6240 SUVR was increased in the ischemic lesion compared with 20 age-matched healthy controls (median age 71.5 years [IQR: 66-76 years]; ratiolesion/controls = 1.62 ± 0.54; 1-sample t test: p = 0.0015) and gradually decreased in the surrounding tissue (1-way within-subject analysis of variance [F{1.2, 14.8} = 18.0, p = 0.00043]). DISCUSSION: These findings suggest that NFT may form after ischemic stroke and spread in the peri-ischemic brain parenchyma. Further follow-up is required to gain more insight into the spatial and temporal dynamics of this tauopathy after ischemic stroke.

18F-AlF-NOTA-Octreotide Outperforms 68Ga-DOTATATE/NOC PET in Neuroendocrine Tumor Patients: Results from a Prospective, Multicenter Study.

18F-labeled somatostatin analogs (SSAs) could represent a valid alternative to the current gold standard, 68Ga-labeled SSAs, for somatostatin receptor imaging in patients with neuroendocrine tumors (NETs), given their logistic advantages. Recently, 18F-AlF-NOTA-octreotide (18F-AlF-OC) has emerged as a promising candidate, but a thorough comparison with 68Ga-DOTA-SSA in large patient groups is needed. This prospective, multicenter trial aims to demonstrate noninferiority of 18F-AlF-OC compared with 68Ga-DOTA-SSA PET in NET patients (ClinicalTrials.gov, NCT04552847). Methods: Seventy-five patients with histologically confirmed NET and routine clinical 68Ga-DOTATATE (n = 56) or 68Ga-DOTANOC (n = 19) PET, performed within a 3-mo interval of the study scan (median, 7 d; range, -30 to +32 d), were included. Patients underwent a whole-body PET 2 h after intravenous injection of 4 MBq/kg of 18F-AlF-OC. A randomized, masked consensus read was performed by 2 experienced readers to count tumor lesions. After unmasking, the detection ratio (DR) was determined for each scan, that is, the fraction of lesions detected on a scan compared with the union of lesions of both scans. The differential DR (DDR; difference in DR between 18F-AlF-OC and 68Ga-DOTATATE/NOC) per patient was calculated. Tracer uptake was evaluated by comparing SUVmax and tumor-to-background ratios in concordant lesions. Results: In total, 4,709 different tumor lesions were detected: 3,454 with 68Ga-DOTATATE/NOC and 4,278 with 18F-AlF-OC. The mean DR with 18F-AlF-OC was significantly higher than with 68Ga-DOTATATE/NOC (91.1% vs. 75.3%; P < 10-5). The resulting mean DDR was 15.8%, with a lower margin of the 95% CI (95% CI, 9.6%-22.0%) higher than -15%, which is the prespecified boundary for noninferiority. The mean DDRs for the 68Ga-DOTATATE and 68Ga-DOTANOC subgroups were 11.8% (95% CI, 4.3-19.3) and 27.5% (95% CI, 17.8-37.1), respectively. The mean DDR for most organs was higher than zero, except for bone lesions (mean DDR, -2.8%; 95% CI, -17.8 to 12.2). No significant differences in mean SUVmax were observed (P = 0.067), but mean tumor-to-background ratio was significantly higher with 18F-AlF-OC than with 68Ga-DOTATATE/NOC (31.7 ± 36.5 vs. 25.1 ± 32.7; P = 0.001). Conclusion: 18F-AlF-OC is noninferior and even superior to 68Ga-DOTATATE/NOC PET in NET patients. This validates 18F-AlF-OC as an option for clinical practice somatostatin receptor PET.

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. This overview article aims to provide research advances in disease model, targeted therapy, blood brain barrier (BBB) opening strategies, imaging and its incorporation with artificial intelligence, external radiotherapy, and internal targeted radionuclide theragnostics. Finally, a distinct type of BM, leptomeningeal metastasis is also covered.

3p-C-NETA: A versatile and effective chelator for development of Al18F-labeled and therapeutic radiopharmaceuticals.

Background: Radiolabeled somatostatin analogues (e.g. [68Ga]Ga-DOTATATE and [177Lu]Lu-DOTATATE) have been used to diagnose, monitor, and treat neuroendocrine tumour (NET) patients with great success. [18F]AlF-NOTA-octreotide, a promising 18F-labeled somatostatin analogue and potential alternative for 68Ga-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 (e.g. Al18F-method in combination with therapeutic radiometals 213Bi/177Lu) or identical (e.g. complementary Tb-radionuclides) pharmacokinetic properties, allowing for accurate personalised dosimetry estimation and radionuclide therapy of NET patients. In this study we evaluated 3p-C-NETA, as potential theranostic Al18F-chelator and present first results of radiosynthesis and preclinical evaluation of [18F]AlF-3p-C-NETA-TATE. Methods: 3p-C-NETA was synthesized and radiolabeled with diagnostic (68Ga, Al18F) or therapeutic (177Lu, 161Tb, 213Bi, 225Ac and 67Cu) radionuclides at different temperatures (25-95 °C). The in vitro stability of the corresponding radiocomplexes was determined in phosphate-buffered saline (PBS) and human serum. 3p-C-NETA-TATE was synthesized using standard solid/liquid-phase peptide synthesis. [18F]AlF-3p-C-NETA-TATE was synthesized in an automated AllinOne® synthesis module and the in vitro stability of [18F]AlF-3p-C-NETA-TATE was evaluated in formulation buffer, PBS and human serum. [18F]AlF-3p-C-NETA-TATE pharmacokinetics were evaluated using µPET/MRI in healthy rats, with [18F]AlF-NOTA-Octreotide as benchmark. Results: 3p-C-NETA quantitatively sequestered 177Lu, 213Bi and 67Cu at 25 °C while heating was required to bind Al18F, 68Ga, 161Tb and 225Ac efficiently. The [18F]AlF-, [177Lu]Lu- and [161Tb]Tb-3p-C-NETA-complex showed excellent in vitro stability in both PBS and human serum over the study period. In contrast, [67Cu]Cu- and [225Ac]Ac-, [68Ga]Ga-3p-C-NETA were stable in PBS, but not in human serum. [18F]AlF-3p-C-NETA-TATE was obtained in good radiochemical yield and radiochemical purity. [18F]AlF-3p-C-NETA-TATE displayed good in vitro stability for 4 h in all tested conditions. Finally, [18F]AlF-3p-C-NETA-TATE showed excellent pharmacokinetic properties comparable with the results obtained for [18F]AlF-NOTA-Octreotide. Conclusions: 3p-C-NETA is a versatile chelator that can be used for both diagnostic applications (Al18F) and targeted radionuclide therapy (213Bi, 177Lu, 161Tb). It has the potential to be the new theranostic chelator of choice for clinical applications in nuclear medicine.

Biodistribution and dosimetry in human healthy volunteers of the PET radioligands [11C]CHDI-00485180-R and [11C]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 [11C]CHDI-00485180-R ([11C]CHDI-180R) and [11C]CHDI-00485626 ([11C]CHDI-626), two tracers designed for PET imaging of aggregated mHTT in the brain that have been validated in preclinical models. METHODS: Biodistribution and radiation dosimetry studies were performed in 3 healthy volunteers (age 25.7 ± 0.5 years; 2 F) for [11C]CHDI-180R and in 3 healthy volunteers (age 35.3 ± 6.8 years; 2 F) for [11C]CHDI-626 using sequential whole-body PET-CT. Source organs were delineated in 3D using combined PET and CT data. Individual organ doses and effective doses were determined using OLINDA 2.1. RESULTS: There were no clinically relevant adverse events. The mean effective dose (ED) for [11C]CHDI-180R was 4.58 ± 0.65 µSv/MBq, with highest absorbed doses for liver (16.9 µGy/MBq), heart wall (15.9 µGy/MBq) and small intestine (15.8 µGy/MBq). Mean ED for [11C]CHDI-626 was 5.09 ± 0.06 µSv/MBq with the highest absorbed doses for the gallbladder (26.5 µGy/MBq), small intestine (20.4 µGy/MBq) and liver (19.6 µGy/MBq). Decay-corrected brain uptake curves showed promising kinetics for [11C]CHDI-180R, but for [11C]CHDI-626 an increasing signal over time was found, probably due to accumulation of a brain-penetrant metabolite. CONCLUSION: [11C]CHDI-180R and [11C]CHDI-626 are safe for in vivo PET imaging in humans. The estimated radiation burden is in line with most 11C-ligands. While [11C]CHDI-180R has promising kinetic properties in the brain, [11C]CHDI-626 is not suitable for human in vivo mHTT PET due to the possibility of a radiometabolite accumulating in brain parenchyma. TRIAL REGISTRATION: EudraCT number 2020-002129-27. CLINICALTRIALS: gov NCT05224115 (retrospectively registered).

Structure-Based Design, Optimization, and Development of [18F]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 18F-labeled radioligand starting from the structure of the known naphthyrid-2-one CB2R ligands. Compound 28 (LU13) was identified with the highest binding affinity and selectivity versus CB1R (CB2RKi = 0.6 nM; CB1RKi/CB2RKi > 1000) and was selected for radiolabeling with fluorine-18 and biological characterization. The new radioligand [18F]LU13 showed high CB2R affinity in vitro as well as high metabolic stability in vivo. PET imaging with [18F]LU13 in a rat model of vector-based/-related hCB2R overexpression in the striatum revealed a high signal-to-background ratio. Thus, [18F]LU13 is a novel and highly promising PET radioligand for the imaging of upregulated CB2R expression under pathological conditions in the brain.

Lack of association between bridging integrator 1 (BIN1) rs744373 polymorphism and tau-PET load in cognitively intact older adults.

INTRODUCTION: The bridging integrator 1(BIN1) rs744373 risk polymorphism has been linked to increased [18F]AV1451 signal in non-demented older adults (ie., mild cognitive impairment [MCI] plus cognitively normal [CN] individuals). However, the association of BIN1 with in vivo tau, amyloid beta (Aß) burden, and cognitive impairment in the asymptomatic stage of Alzheimer's disease (AD) remains unknown. METHODS: The BIN1 effect on [18F]AV1451 binding was evaluated in 59 cognitively normal (CN) participants (39% apolipoprotein E [APOE ε4]) from the Flemish Prevent AD Cohort KU Leuven (F-PACK), as well as in 66 Alzheimer's Disease Neuroimaging Initiative (ADNI) CN participants, using voxelwise and regional statistics. For comparison, 52 MCI patients from ADNI were also studied. RESULTS: Forty-four percent of F-PACK participants were BIN1 rs744373 risk-allele carriers, 21% showed high amyloid burden, and 8% had elevated [18F]AV1451 binding. In ADNI, 53% and 50% of CNs and MCIs, respectively, carried the BIN1 rs744373 risk-allele. Amyloid positivity was present in 23% of CNs and 51% of MCIs, whereas 2% of CNs and 35% of MCIs showed elevated [18F]AV1451 binding. There was no significant effect of BIN1 on voxelwise or regional [18F]AV1451 in F-PACK or ADNI CNs, or in the pooled CN sample. No significant association between BIN1 and [18F]AV1451 was obtained in ADNI MCI patients. However, in the MCI group, numerically higher [18F]AV1451 binding was observed in the BIN1 risk-allele group compared to the BIN1 normal group in regions corresponding to more progressed tau pathology. DISCUSSION: We could not confirm the association between BIN1 rs744373 risk-allele and elevated [18F]AV1451 signal in CN older adults or MCI. Numerically higher [18F]AV1451 binding was observed, however, in the MCI BIN1 risk-allele group, indicating that the previously reported positive effect may be confounded by group. Therefore, when studying how the BIN1 risk polymorphism influences AD pathogenesis, a distinction should be made between asymptomatic, MCI, and dementia stages of AD.