Search

To date, the imaging and diagnosis of hepatocellular carcinoma (HCC) rely on CT/MRI, which have well-known limitations. Glypican-3 (GPC3) is a cell surface receptor highly expressed by HCC but not by normal or cirrhotic liver tissue. Here we report initial clinical results of GPC3-targeted PET imaging with [ 68 Ga]Ga-DOTA-RYZ-GPC3 (RAYZ-8009), a peptide-based GPC3 ligand in patients with known or suspected HCC. Methods: [ 68 Ga]Ga-RAYZ-8009 was obtained after labeling the peptide precursor with 68 Ga from a 68 Ge/ 68 Ga generator and heating at 90°C for 10 min followed by sterile filtration. After administration of [ 68 Ga]Ga-RAYZ-8009, a dynamic or static PET/CT scan was acquired between 45 min and 4 h after administration. Radiotracer uptake was measured by SUVs for the following tissues: suspected or actual HCC or hepatoblastoma lesions, non-tumor-bearing liver, renal cortex, blood pool in the left ventricle, and gastric fundus. Additionally, tumor-to-healthy-liver ratios (TLRs) were calculated. Results: Twenty-four patients (5 patients in the dynamic protocol; 19 patients in the static protocol) were scanned. No adverse events occurred. Two patients had no lesion detected and did not have HCC during follow-up. In total, 50 lesions were detected and analyzed. The mean SUV max of these lesions was 19.6 (range, 2.7-95.3), and the mean SUV mean was 10.1 (range, 1.0-49.2) at approximately 60 min after administration. Uptake in non-tumor-bearing liver and blood pool rapidly decreased over time and became negligible 45 min after administration (mean SUV mean , <1.6), with a continuous decline to 4 h after administration (mean SUV mean , 1.0). The opposite was observed for HCC lesions, for which SUVs and TLRs continuously increased for up to 4 h after administration. In individual lesion analysis, TLR was the highest between 60 and 120 min after administration. Uptake in the gastric fundus gradually increased for up to 45 min (to an SUV max of 31.3) and decreased gradually afterward. Conclusion: [ 68 Ga]Ga-RAYZ-8009 is safe and allows for high-contrast imaging of GPC3-positive HCC, with rapid clearance from most normal organs. Thereby, [ 68 Ga]Ga-RAYZ-8009 is promising for HCC diagnosis and staging. Further research is warranted., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Ovarian cancer mortality rates have not decreased significantly in the past years. As most women are still diagnosed in an advanced stage, there is a need for new treatment strategies for recurrent disease. A potentially new developing targeted approach, theranostics, combines diagnostics and treatment using radiopharmaceuticals. Through target receptors, imaging and treatment of malignant tissue can be achieved. For ovarian malignancy, the follicle-stimulating hormone (FSH) receptor may serve as a possible target since expression appears to be limited to ovarian cells. In this systematic review, we aim to gather all available literature on the expression of the FSH receptor in ovarian tumors. Pubmed, Embase and the Cochrane databases were searched until December 2023 for eligible studies. The search yielded 41 studies, mostly regarding serous carcinomas, sex cord-stromal tumors (SCSTs) and cell lines of serous and SCSTs. Various techniques were used to analyze the expression of the FSH receptor. For serous carcinomas, conflicting results on the expression of the FSH receptor were found. Studies on SCSTs, mainly studying the subtype of granulosa cell tumors, all showed positive expression of the FSH receptor. In the cell lines studies, the KGN cell line derived from a granulosa cell tumor shows positive expression in all studies. Available studies show that SCSTs express the FSH receptor. A theranostic approach targeting the FSH receptor may, therefore, provide a useful new approach for this malignancy with limited therapeutic options in recurrent disease.

Background: Mutations in the epidermal growth factor receptor (EGFR) kinase domain are common in non-small cell lung cancer. Conventional tyrosine kinase inhibitors target the mutation site in the ATP binding pocket, thereby inhibiting the receptor's function. However, subsequent treatment resistance mutations in the ATP binding site are common. The EGFR allosteric inhibitor, EAI045, is proposed to have an alternative mechanism of action, disrupting receptor signaling independent of the ATP-binding site. The antibody cetuximab is hypothesized to increase the number of accessible allosteric pockets for EAI045, thus increasing the potency of the inhibitor. This work aimed to gain further knowledge on pharmacokinetics, the EGFR mutation-targeting potential, and the influence of cetuximab on the uptake by radiolabeling EAI045 with carbon-11 and tritium., Results: 2-(5-fluoro-2-hydroxyphenyl)-2-((2-iodobenzyl)amino)-N-(thiazol-2-yl)acetamide and 2-(5-fluoro-2-hydroxyphenyl)-N-(5-iodothiazol-2-yl)-2-(1-oxoisoindolin-2-yl)acetamide were synthesized as precursors for the carbon-11 and tritium labeling of EAI045, respectively. [ 11 C]EAI045 was synthesized using [ 11 C]CO in a palladium-catalyzed ring closure in a 10 ± 1% radiochemical yield (decay corrected to end of [ 11 C]CO 2 production), > 97% radiochemical purity and 26 ± 1 GBq/µmol molar activity (determined at end of synthesis) in 51 min. [ 3 H]EAI045 was synthesized by a tritium-halogen exchange in a 0.2% radiochemical yield, 98% radiochemical purity, and 763 kBq/nmol molar activity. The ability of [ 11 C]EAI045 to differentiate between L858R/T790M mutated EGFR expressing H1975 xenografts and wild-type EGFR expressing A549 xenografts was evaluated in female nu/nu mice. The uptake was statistically significantly higher in H1975 xenografts compared to A549 xenografts (0.45 ± 0.07%ID/g vs. 0.31 ± 0.10%ID/g, P = 0.0166). The synergy in inhibition between EAI045 and cetuximab was evaluated in vivo and in vitro. While there was some indication that cetuximab influenced the uptake of [ 3 H]EAI045 in vitro, this could not be confirmed in vivo when tumor-bearing mice were administered cetuximab (0.5 mg), 24 h prior to injection of [ 11 C]EAI045., Conclusions: EAI045 was successfully labeled with tritium and carbon-11, and the in vivo results indicated [ 11 C]EAI045 may be able to distinguish between mutated and non-mutated EGFR in non-small cell lung cancer mouse models. Cetuximab was hypothesized to increase EAI045 uptake; however, no significant effect was observed on the uptake of [ 11 C]EAI045 in vivo or [ 3 H]EAI045 in vitro in H1975 xenografts and cells., (© 2024. The Author(s).)

Radiolabeled amino acids (AAs), their derivatives, and peptides are essential radiotracers in nuclear imaging. Despite its potential, the preparation of enantiopure radiopharmaceuticals poses several challenges, demanding a great need for rapid and stereocontrolled reactions. This chapter describes a highly stereoselective carbon-11 alkylation of Schiff bases, to obtain radiolabeled AAs and small peptides. The method uses chiral quaternary ammonium salt phase-transfer catalyst with two alkylating agents, namely, [ 11 C]methyl iodide and [ 11 C]benzyl iodide. This methodology allows the radiolabeling of AAs and peptides with excellent regioselectivity and enantiomeric or diastereomeric excess., (© 2024. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Sentinel lymph node (SLN) biopsy is rarely used for thyroid carcinoma staging. This is due to challenges associated with conventional Tc-99m-labeled tracers, often producing a large hotspot at the injection site, potentially hiding nearby SLNs (shine-through effect). The aim of this study was to demonstrate the feasibility and effectiveness of SLN visualization using the new PET tracer [ 68 Ga]Ga-tilmanocept., Methods: Patients with thyroid carcinoma underwent ultrasound-guided peritumoral injection of [ 68 Ga]Ga-tilmanocept and ICG-[ 99m Tc]Tc-nanocolloid. [ 68 Ga]Ga-tilmanocept PET/CT scans were conducted at 15 min and 60 min post-injection to visualize the SLNs. SLN biopsy was performed using ICG-[ 99m Tc]TC-nanocolloid for intraoperative identification. The corresponding lymph node level was resected for reference., Results: Seven differentiated thyroid carcinoma (DTC) and 3 medullary thyroid carcinoma (MTC) patients were included, of which 6 were clinically node-negative. The median number of SLNs detected on [ 68 Ga]Ga-tilmanocept PET/CT and resected was 3 (range 1-4) and 3 (range 1-5), respectively. Eight SLNs were found on PET/CT in the central compartment and 19 in the lateral compartment. The SLN procedure detected (micro)metastases in all patients except one. Seventeen of 27 pathologically assessed SLNs were positive, 8 negative, and 2 did not contain lymph node tissue, which led to upstaging in 5 out of 6 clinically node-negative patients., Conclusions: [ 68 Ga]Ga-tilmanocept PET/CT identified SLNs in all patients, mainly in the lateral neck. The SLNs were successfully surgically detected and resected using ICG-[ 99m Tc]Tc-nanocolloid. This technique has the potential to improve neck staging, enabling more personalized treatment of thyroid cancer according to the lymph node status., Trial Registration: 2021-002470-42 (EudraCT)., (© 2023. The Author(s).)

Brigatinib, a tyrosine kinase inhibitor (TKI) with specificity for gene rearranged anaplastic lymphoma kinase (ALK), such as the EML4-ALK, has shown a potential to inhibit mutated epidermal growth factor receptor (EGFR). In this study, N -desmethyl brigatinib was successfully synthesized as a precursor in five steps. Radiolabeling with [ 11 C]methyl iodide produced [ methylpiperazine - 11 C]brigatinib in a 10 ± 2% radiochemical yield, 91 ± 17 GBq/μmol molar activity, and ≥95% radiochemical purity in 49 ± 4 min. [ Methylpiperazine - 11 C]brigatinib was evaluated in non-small cell lung cancer xenografted female nu/nu mice. An hour post-injection (p.i.), 87% of the total radioactivity in plasma originated from intact [ methylpiperazine - 11 C]brigatinib. Significant differences in tumor uptake were observed between the endogenously EML4-ALK mutated H2228 and the control xenograft A549. The tumor-to-blood ratio in H2228 xenografts could be reduced by pretreatment with ALK inhibitor crizotinib. Tracer uptake in EGFR Del19 mutated HCC827 and EML4-ALK fusion A549 was not significantly different from uptake in A549 xenografts.

Introduction: Osimertinib is a third-generation tyrosine kinase inhibitor (TKI) that is able to inhibit the EGFR treatment resistance mutation T790M and primary EGFR mutations Del19 and L858R. The aim of the study was to evaluate the potential of carbon-11 labeled osimertinib to be used as a tracer for the PET imaging of tumors bearing the T790M mutation., Methods: Osimertinib was labeled with carbon-11 at two positions, and the effect of the labeling position on the metabolism and biodistribution was studied in female nu/nu mice. The mutation status specificity of osimertinib was confirmed in vitro in a cell growth inhibition experiment, and the tumor-targeting potential of the carbon-11 isotopologues was evaluated using female nu/nu mice xenografted with NSCLC cell lines; the wild-type EGFR expressing A549, the primary Del19 EGFR mutated HCC827 and the resistance T790M/L858R mutated H1975. One of the osimertinib tracers was selected based on the results acquired and evaluated for tracer specificity and selectivity by assessment of tumor uptake in a PET study where HCC827 tumor-bearing mice were pretreated with osimertinib or afatinib., Results: [Methylindole- 11 C]- and [dimethylamine- 11 C]osimertinib were synthesized by 11 C-methylation of precursors AZ5104 and AZ7550, respectively. Rapid metabolism of both analogs of [ 11 C]osimertinib was observed. Although the tumor uptake and retention of [methylindole- 11 C]- and [dimethylamine- 11 C]osimertinib in tumors were similar, the tumor-to-muscle ratios appeared to be higher for [methylindole- 11 C]osimertinib. The highest uptake, tumor-to-blood, and tumor-to-muscle ratio were observed in the Del19 EGFR mutated HCC827 tumors. However, the specificity and selectivity of [methylindole- 11 C]osimertinib PET could not be demonstrated in HCC827 tumors. The uptake of [methylindole- 11 C]osimertinib was not significantly higher in T790M resistance mutated H1975 xenografts compared to the negative control cell line A549., Conclusions: Osimertinib was successfully labeled at two positions with carbon-11, yielding two EGFR PET tracers, [methylindole- 11 C]osimertinib and [dimethylamine- 11 C]osimertinib. The preclinical evaluation demonstrated uptake and retention in three NSCLC xenografts; A549, HCC827, and H1975. The highest uptake was observed in the primary Del19 EGFR mutated HCC827. The ability of [methylindole- 11 C]osimertinib to distinguish between the T790M resistance mutated H1975 xenografts and the wild-type EGFR expressing A549 could not be confirmed in the ex vivo study., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: A.D. Windhorst is editor-in-chief of Nuclear Medicine & Biology. Daniëlle A.M. Heideman is a minority shareholder of Self-screen B.V., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Transforming growth factor β (TGFβ) activity is perturbed in remodelled pulmonary vasculature of patients with pulmonary arterial hypertension (PAH), cancer, vascular diseases and developmental disorders. Inhibition of TGFβ, which signals via activin receptor-like kinase 5 (ALK5), prevents progression and development of experimental PAH. The purpose of this study was to assess two ALK5 targeting positron emission tomography (PET) tracers ([ 11 C]LR111 and [ 18 F]EW-7197) for imaging ALK5 in monocrotaline (MCT)- and Sugen/hypoxia (SuHx)-induced PAH. Both tracers were subjected to extensive in vitro and in vivo studies. [ 11 C]LR111 showed the highest metabolic stability, as 46 ± 2% of intact tracer was still present in rat blood plasma after 60 min. In autoradiography experiments, [ 11 C]LR111 showed high ALK5 binding in vitro compared with controls, 3.2 and 1.5 times higher in SuHx and MCT, respectively. In addition, its binding could be blocked by SB431542, an adenosine triphosphate competitive ALK5 kinase inhibitor. However, [ 18 F]EW-7197 showed the best in vivo results. 15 min after injection, uptake was 2.5 and 1.4 times higher in the SuHx and MCT lungs, compared with controls. Therefore, [ 18 F]EW-7197 is a promising PET tracer for ALK5 imaging in PAH., (© 2023. The Author(s).)

Purpose: Meta-[ 18 F]fluorobenzylguanidine ([ 18 F]mFBG) is a positron emission tomography (PET) radiotracer that allows for fast and high-resolution imaging of tumours expressing the norepinephrine transporter. This pilot study investigates the feasibility of [ 18 F]mFBG PET-CT for imaging in neuroblastoma., Methods: In a prospective, single-centre study, we recruited children with neuroblastoma, referred for meta-[ 123 I]iodobenzylguanidine ([ 123 I]mIBG) scanning, consisting of total body planar scintigraphy in combination with single-photon emission computed tomography-CT (SPECT-CT). Within two weeks of [ 123 I]mIBG scanning, total body PET-CTs were performed at 1 h and 2 h after injection of [ 18 F]mFBG (2 MBq/kg). Detected tumour localisations on scan pairs were compared. Soft tissue disease was quantified by number of lesions and skeletal disease by SIOPEN score., Results: Twenty paired [ 123 I]mIBG and [ 18 F]mFBG scans were performed in 14 patients (median age 4.9 years, n = 13 stage 4 disease and n = 1 stage 4S). [ 18 F]mFBG injection was well tolerated and no related adverse events occurred in any of the patients. Mean scan time for [ 18 F]mFBG PET-CT (9.0 min, SD 1.9) was significantly shorter than for [ 123 I]mIBG scanning (84.5 min, SD 10.5), p < 0.01. Most tumour localisations were detected on the 1 h versus 2 h post-injection [ 18 F]mFBG PET-CT. Compared to [ 123 I]mIBG scanning, [ 18 F]mFBG PET-CT detected a higher, equal, and lower number of soft tissue lesions in 40%, 55%, and 5% of scan pairs, respectively, and a higher, equal, and lower SIOPEN score in 55%, 30%, and 15% of scan pairs, respectively. On average, two more soft tissue lesions and a 6-point higher SIOPEN score were detected per patient on [ 18 F]mFBG PET-CT compared to [ 123 I]mIBG scanning., Conclusion: Results of this study demonstrate feasibility of [ 18 F]mFBG PET-CT for neuroblastoma imaging. More neuroblastoma localisations were detected on [ 18 F]mFBG PET-CT compared to [ 123 I]mIBG scanning. [ 18 F]mFBG PET-CT shows promise for future staging and response assessment in neuroblastoma., Trial Registration: Dutch Trial Register NL8152., (© 2022. The Authors.)

Implant infections caused by Staphylococcus aureus are difficult to treat due to biofilm formation, which complicates surgical and antibiotic treatment. We introduce an alternative approach using monoclonal antibodies (mAbs) targeting S. aureus and provide evidence of the specificity and biodistribution of S. - aureus -targeting antibodies in a mouse implant infection model. The monoclonal antibody 4497-IgG1 targeting wall teichoic acid in S. aureus was labeled with indium-111 using CHX-A"-DTPA as a chelator. Single Photon Emission Computed Tomography/computed tomographyscans were performed at 24, 72 and 120 h after administration of the 111 In-4497 mAb in Balb/cAnNCrl mice with a subcutaneous implant that was pre-colonized with S. aureus biofilm. The biodistribution of this labelled antibody over various organs was visualized and quantified using SPECT/CT imaging, and was compared to the uptake at the target tissue with the implanted infection. Uptake of the 111 In-4497 mAbs at the infected implant gradually increased from 8.34 %ID/cm 3 at 24 h to 9.22 %ID/cm 3 at 120 h. Uptake at the heart/blood pool decreased over time from 11.60 to 7.58 %ID/cm 3 , whereas the uptake in the other organs decreased from 7.26 to less than 4.66 %ID/cm 3 at 120 h. The effective half-life of 111 In-4497 mAbs was determined to be 59 h. In conclusion, 111 In-4497 mAbs were found to specifically detect S. aureus and its biofilm with excellent and prolonged accumulation at the site of the colonized implant. Therefore, it has the potential to serve as a drug delivery system for the diagnostic and bactericidal treatment of biofilm., Competing Interests: Ruud M. Ramakers has stock appreciation rights at MILabs B.V. Freek J. Beekman is a shareholder at MILabs B.V. The other authors declare that no competing interests exist.

Biologicals, such as antibodies or antibody-fragments e.g. nanobodies, have changed the landscape of cancer therapy and can be used in combination with traditional cancer treatments. They have been demonstrated to be excellent vehicles for molecular imaging. Several biologicals for nuclear imaging of adult cancer may be used in combination with (nuclear) therapy. Though it's great potential, molecular imaging using biologicals is rarely applied in paediatric oncology. This paper describes the current status of biologicals as radiopharmaceuticals for childhood cancer. Furthermore, the importance and potential for developing additional biological theranostics as opportunity to image and treat childhood cancer is discussed., Competing Interests: Conflict of interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

The transforming growth factor β (TGFβ) pathway plays a complex role in cancer biology, being involved in both tumour suppression as well as promotion. Overactive TGFβ signalling has been linked to multiple diseases, including cancer, pulmonary arterial hypertension, and fibrosis. One of the key meditators within this pathway is the TGFβ type I receptor, also termed activin receptor-like kinase 5 (ALK5). ALK5 expression level is a key determinant of TGFβ signalling intensity and duration, and perturbation has been linked to diseases. A validated ALK5 positron emission tomography (PET) tracer creates an opportunity, therefore, to study its role in human diseases. To develop ALK5 PET tracers, two small molecule ALK5 kinase inhibitors were selected as lead compounds, which were labelled with carbon-11 and fluorine-18, respectively. [ 11 C]LR111 was synthesized with a yield of 17 ± 6%, a molar activity of 126 ± 79 GBq·μmol -1 and a purity of >95% (n = 44). [ 18 F]EW-7197 was synthesized with a yield of 10 ± 5%, a molar activity of 183 ± 126 GBq·μmol -1 and a purity of >95% (n = 11). Metabolic stability was evaluated in vivo in mice, showing 39 ± 2% of intact [ 11 C]LR111 and 21 ± 2% of intact [ 18 F]EW-7197 in blood plasma at 45 min p.i. In vitro binding experiments were conducted in breast cancer MDA-MB-231 and lung cancer A431 cell lines. In addition, both tracers were used for PET imaging in MDA-MB-231 xenograft models. Selective uptake of [ 18 F]EW-7197 and [ 11 C]LR111 was observed in MDA-MB-231 cells, in the MDA-MB-231 tumour xenografts in vivo and in the autoradiograms. As [ 11 C]LR111 and [ 18 F]EW-7197 showed selectivity of binding to ALK5 in vivo and in vitro. Both tracers are thereby valuable tools for the detection of ALK5 activity., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Glutamine is consumed by rapidly proliferating cells and can provide the carbon and nitrogen required for growth through various metabolic pathways. However, delineating the metabolic fate of glutamine is challenging to interrogate in vivo. Hyperpolarized magnetic resonance, by providing high transient nuclear magnetic resonance signals, provides an approach to measure fast biochemical processes in vivo. Aminohydrolysis of glutamine at carbon-5 plays an important role in providing nitrogen and carbon for multiple pathways. Here, we provide a synthetic strategy for isotope-enriched forms of glutamine that prolongs glutamine-C5 relaxation times and thereby reveals in vivo reactions involving carbon-5. We investigate multiple enrichment states, finding [5-13C,4,4-2H2,5-15N]-L-glutamine to be optimal for hyperpolarized measurement of glutamine conversion to glutamate in vivo. Leveraging this compound, we explore pancreatic cancer glutamine metabolism in vivo. Taken together, this work provides a means for studying glutamine metabolic flux in vivo and demonstrates on-target effects of metabolic enzyme inhibitors.

Multiple small molecule PET tracers have been developed for the imaging of the epidermal growth factor receptor (EGFR). These tracers target the tyrosine kinase (TK) domain of the receptor and have been used for both quantifying EGFR expression and to differentiate between EGFR mutational statuses. However, the approaches for in vivo evaluation of these tracers are diverse and have resulted in data that are hard to compare. In this review, we analyze the historical development of the in vivo evaluation approaches, starting from the first EGFR TK PET tracer [ 11 C]PD153035 to tracers developed based on TK inhibitors used for the clinical treatment of mutated EGFR expressing non-small cell lung cancer like [ 11 C]erlotinib and [ 18 F]afatinib. The evaluation of each tracer has been compiled to allow for a comparison between studies and ultimately between tracers. The main challenges for each group of tracers are thereafter discussed. Finally, this review addresses the challenges that need to be overcome to be able to efficiently drive EGFR PET imaging forward.

Introduction: The assessment of ex vivo biodistribution is the preferred method for quantification of radiotracers biodistribution in preclinical models, but is not in line with current ethics on animal research. PET imaging allows for noninvasive longitudinal evaluation of tracer distribution in the same animals, but systemic comparison with ex vivo biodistribution is lacking. Our aim was to evaluate the potential of preclinical PET imaging for accurate tracer quantification, especially in tumor models., Methods: NEMA NU 4-2008 phantoms were filled with 11 C, 68 Ga, 18 F, or 89 Zr solutions and scanned in Mediso nanoPET/CT and PET/MR scanners until decay. N87 tumor-bearing mice were i.v. injected with either [ 18 F]FDG (~ 14 MBq), kept 50 min under anesthesia followed by imaging for 20 min, or with [ 89 Zr]Zr-DFO-NCS-trastuzumab (~ 5 MBq) and imaged 3 days post-injection for 45 min. After PET acquisition, animals were killed and organs of interest were collected and measured in a γ-counter to determine tracer uptake levels. PET data were reconstructed using TeraTomo reconstruction algorithm with attenuation and scatter correction and regions of interest were drawn using Vivoquant software. PET imaging and ex vivo biodistribution were compared using Bland-Altman plots., Results: In phantoms, the highest recovery coefficient, thus the smallest partial volume effect, was obtained with 18 F for both PET/CT and PET/MR. Recovery was slightly lower for 11 C and 89 Zr, while the lowest recovery was obtained with 68 Ga in both scanners. In vivo, tumor uptake of the 18 F- or 89 Zr-labeled tracer proved to be similar irrespective whether quantified by either PET/CT and PET/MR or ex vivo biodistribution with average PET/ex vivo ratios of 0.8-0.9 and a deviation of 10% or less. Both methods appeared less congruent in the quantification of tracer uptake in healthy organs such as brain, kidney, and liver, and depended on the organ evaluated and the radionuclide used., Conclusions: Our study suggests that PET quantification of 18 F- and 89 Zr-labeled tracers is reliable for the evaluation of tumor uptake in preclinical models and a valuable alternative technique for ex vivo biodistribution. However, PET and ex vivo quantification require fully described experimental and analytical procedures for reliability and reproducibility.

Objectives: Non-small cell lung cancer (NSCLC) tumors harboring common (exon19del, L858R) and uncommon (e.g. G719X, L861Q) activating epidermal growth factor receptor (EGFR) mutations are best treated with EGFR tyrosine kinase inhibitors (TKI) such as the first-generation EGFR TKI erlotinib, second-generation afatinib or third-generation osimertinib. However, identifying these patients through biopsy is not always possible. Therefore, our aim was to evaluate whether 18 F-afatinib PET/CT could identify patients with common and uncommon EGFR mutations. Furthermore, we evaluated the relation between tumor 18 F-afatinib uptake and response to afatinib therapy., Materials and Methods: 18 F-afatinib PET/CT was performed in 12 patients: 6 EGFR wild type (WT), 3 EGFR common and 3 EGFR uncommon mutations. Tumor uptake of 18 F-afatinib was quantified using TBR&#95;WB 60-90 (tumor-to-whole blood activity ratio 60-90 min post-injection) for each tumor. Response was quantified per lesion using percentage of change (PC): [(response measurement (RM)-baseline measurement (BM))/BM]×100. Statistical analyses were performed using t-tests, correlation plots and sensitivity/specificity analysis., Results: Twenty-one tumors were identified. Injected dose was 348 ± 31 MBq. Group differences were significant between WT versus EGFR (common and uncommon) activating mutations (p = 0.03). There was no significant difference between EGFR common versus uncommon mutations (p = 0.94). A TBR&#95;WB 60-90 cut-off value of 6 showed the best relationship with response with a sensitivity of 70 %, a specificity of 100 % and a positive predictive value of 100 %., Conclusion: 18 F-afatinib uptake was higher in tumors with EGFR mutations (common and uncommon) compared to WT. Furthermore, a TBR&#95;WB 60-90 cut-off of 6 was found to best predict response to therapy. 18 F-afatinib PET/CT could provide a means to identify EGFR mutation positive patients who benefit from afatinib therapy., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Neuroblastoma is the most common extracranial solid malignancy in children. At diagnosis, approximately 50% of patients present with metastatic disease. These patients are at high risk for refractory or recurrent disease, which conveys a very poor prognosis. During the past decades, nuclear medicine has been essential for the staging and response assessment of neuroblastoma. Currently, the standard nuclear imaging technique is meta -[ 123 I]iodobenzylguanidine ([ 123 I]mIBG) whole-body scintigraphy, usually combined with single-photon emission computed tomography with computed tomography (SPECT-CT). Nevertheless, 10% of neuroblastomas are mIBG non-avid and [ 123 I]mIBG imaging has relatively low spatial resolution, resulting in limited sensitivity for smaller lesions. More accurate methods to assess full disease extent are needed in order to optimize treatment strategies. Advances in nuclear medicine have led to the introduction of radiotracers compatible for positron emission tomography (PET) imaging in neuroblastoma, such as [ 124 I]mIBG, [ 18 F]mFBG, [ 18 F]FDG, [ 68 Ga]Ga-DOTA peptides, [ 18 F]F-DOPA, and [ 11 C]mHED. PET has multiple advantages over SPECT, including a superior resolution and whole-body tomographic range. This article reviews the use, characteristics, diagnostic accuracy, advantages, and limitations of current and new tracers for nuclear medicine imaging in neuroblastoma.

Purpose: Almost all radiolabellings of antibodies with 89 Zr currently employ the hexadentate chelator desferrioxamine (DFO). However, DFO can lead to unwanted uptake of 89 Zr in bones due to instability of the resulting metal complex. DFO*-NCS and the squaramide ester of DFO, DFOSq, are novel analogues that gave more stable 89 Zr complexes than DFO in pilot experiments. Here, we directly compare these linker-chelator systems to identify optimal immuno-PET reagents., Methods: Cetuximab, trastuzumab and B12 (non-binding control antibody) were labelled with 89 Zr via DFO*-NCS, DFOSq, DFO-NCS or DFO*Sq. Stability in vitro was compared at 37 °C in serum (7 days), in formulation solution (24 h ± chelator challenges) and in vivo with N87 and A431 tumour-bearing mice. Finally, to demonstrate the practical benefit of more stable complexation for the accurate detection of bone metastases, [ 89 Zr]Zr-DFO*-NCS and [ 89 Zr]Zr-DFO-NCS-labelled trastuzumab and B12 were evaluated in a bone metastasis mouse model where BT-474 breast cancer cells were injected intratibially., Results: [ 89 Zr]Zr-DFO*-NCS-trastuzumab and [ 89 Zr]Zr-DFO*Sq-trastuzumab showed excellent stability in vitro, superior to their [ 89 Zr]Zr-DFO counterparts under all conditions. While tumour uptake was similar for all conjugates, bone uptake was lower for DFO* conjugates. Lower bone uptake for DFO* conjugates was confirmed using a second xenograft model: A431 combined with cetuximab. Finally, in the intratibial BT-474 bone metastasis model, the DFO* conjugates provided superior detection of tumour-specific signal over the DFO conjugates., Conclusion: DFO*-mAb conjugates provide lower bone uptake than their DFO analogues; thus, DFO* is a superior candidate for preclinical and clinical 89 Zr-immuno-PET.

89 Zr-radiolabelled proteins functionalised with desferrioxamine B are a cornerstone of diagnostic positron emission tomography. In the clinical setting, 89 Zr-labelled proteins are produced manually. Here, we explore the potential of using a microfluidic photochemical flow reactor to prepare 89 Zr-radiolabelled proteins. The light-induced functionalisation and 89 Zr-radiolabelling of human serum albumin ([ 89 Zr]ZrDFO-PEG 3 -Et-azepin-HSA) was achieved by flow photochemistry with a decay-corrected radiochemical yield (RCY) of 31.2 ± 1.3% ( n = 3) and radiochemical purity >90%. In comparison, a manual batch photoreactor synthesis produced the same radiotracer in a decay-corrected RCY of 59.6 ± 3.6% ( n = 3) with an equivalent RCP > 90%. The results indicate that photoradiolabelling in flow is a feasible platform for the automated production of protein-based 89 Zr-radiotracers, but further refinement of the apparatus and optimisation of the method are required before the flow process is competitive with manual reactions.

In theranostics (i.e., therapy and diagnostics) radiopharmaceuticals are used for both therapeutic and diagnostic purposes by targeting one specific tumor receptor. Biologically relevant compounds, e.g., receptor ligands or drugs, are labeled with radionuclides to form radiopharmaceuticals. The possible applications are multifold: visualization of biological processes or tumor biology in vivo , diagnosis and tumor staging, therapy planning, and treatment of specific tumors. Theranostics research is multidisciplinary and allows for the rapid translation of potential tumor targets from preclinical research to "first-in-man" clinical studies. In the last decade, the use of theranostics has seen an unprecedented value for adult cancer patients. Several radiopharmaceuticals are routinely used in clinical practice (e.g., [ 68 Ga/ 177 Lu]DOTATATE), and dozens are under (pre)clinical development. In contrast to these successes in adult oncology, theranostics have scarcely been developed to diagnose and treat pediatric cancers. To date, [ 123/131 I]meta-iodobenzylguanidine ([ 123/131 I]mIBG) is the only available and approved theranostic in pediatric oncology. mIBG targets the norepinephrine transporter, expressed by neuroblastoma tumors. For most pediatric tumors, including neuroblastoma, there is a clear need for novel and improved radiopharmaceuticals for imaging and therapy. The strategy of theranostics for pediatric oncology can be divided in (1) the improvement of existing theranostics, (2) the translation of theranostics developed in adult oncology for pediatric purposes, and (3) the development of novel theranostics for pediatric tumor-specific targets. Here, we describe the recent advances in theranostics development in pediatric oncology and shed a light on how this methodology can affect diagnosis and provide additional treatment options for these patients., (Copyright © 2020 Poot, Lam and van Noesel.)

Fenretinide (4-HPR) is a synthetic derivative of all-trans-retinoic acid (ATRA) characterised by improved therapeutic properties and toxicological profile relative to ATRA. 4-HPR has been mostly investigated as an anti-cancer agent, but recent studies showed its promising therapeutic potential for preventing metabolic syndrome. Several biological targets are involved in 4-HPR's activity, leading to the potential use of this molecule for treating different pathologies. However, although 4-HPR displays quite well-understood multitarget promiscuity with regards to pharmacology, interpreting its precise physiological role remains challenging. In addition, despite promising results in vitro, the clinical efficacy of 4-HPR as a chemotherapeutic agent has not been satisfactory so far. Herein, we describe the preparation of a library of 4-HPR analogues, followed by the biological evaluation of their anti-cancer and anti-obesity/diabetic properties. The click-type analogue 3 b showed good capacity to reduce the amount of lipid accumulation in 3T3-L1 adipocytes during differentiation. Furthermore, it showed an IC 50 of 0.53±0.8 μM in cell viability tests on breast cancer cell line MCF-7, together with a good selectivity (SI=121) over noncancerous HEK293 cells. Thus, 3 b was selected as a potential PET tracer to study retinoids in vivo, and the radiosynthesis of [ 18 F]3b was successfully developed. Unfortunately, the stability of [ 18 F]3b turned out to be insufficient to pursue imaging studies., (© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Introduction: Only a subgroup of non-small cell lung cancer (NSCLC) patients benefit from treatment using epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) such as afatinib. Tumour uptake of [ 18 F]afatinib using positron emission tomography (PET) may identify those patients that respond to afatinib therapy. Therefore, the aim of this study was to find the optimal tracer kinetic model for quantification of [ 18 F]afatinib uptake in NSCLC tumours., Methods: [ 18 F]Afatinib PET scans were performed in 10 NSCLC patients. The first patient was scanned for the purpose of dosimetry. Subsequent patients underwent a 20-min dynamic [ 15 O]H 2 O PET scan (370 MBq) followed by a dynamic [ 18 F]afatinib PET scan (342 ± 24 MBq) of 60 or 90 min. Using the Akaike information criterion (AIC), three pharmacokinetic plasma input models were evaluated with both metabolite-corrected sampler-based input and image-derived (IDIF) input functions in combination with discrete blood samples. Correlation analysis of arterial on-line sampling versus IDIF was performed. In addition, perfusion dependency and simplified measures were assessed., Results: Ten patients were included. The injected activity of [ 18 F]afatinib was 341 ± 37 MBq. Fifteen tumours could be identified in the field of view of the scanner. Based on AIC, tumour kinetics were best described using an irreversible two-tissue compartment model and a metabolite-corrected sampler-based input function (Akaike 50%). Correlation of plasma-based input functions with metabolite-corrected IDIF was very strong (r 2 = 0.93). The preferred simplified uptake parameter was the tumour-to-blood ratio over the 60- to 90-min time interval (TBR 60-90 ). Tumour uptake of [ 18 F]afatinib was independent of perfusion., Conclusion: The preferred pharmacokinetic model for quantifying [ 18 F]afatinib uptake in NSCLC tumours was the 2T3K&#95;vb model. TBR 60-90 showed excellent correlation with this model and is the best candidate simplified method., Trial Registration: https://eudract.ema.europa.eu/ nr 2012-002849-38.

The transforming growth factor β (TGFβ) family of cytokines achieves homeostasis through a careful balance and crosstalk with complex signalling pathways. Inappropriate activation or inhibition of this pathway and mutations in its components are related to diseases such as cancer, vascular diseases, and developmental disorders. Quantitative imaging of expression levels of key regulators within this pathway using positron emission tomography (PET) can provide insights into the role of this pathway in vivo, providing information on underlying pathophysiological processes. PET imaging can also be used to study the drug targeting of this pathway and to detect diseases in which this pathway is disturbed. In this review, we provide an overview of PET tracers available to study the TGFβ signalling pathway. In addition, we discuss future imaging targets for this pathway and possible leads for new PET tracers., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Patient satisfaction with the general practitioner (GP) is lower in older persons with a higher level of complexity of health problems. This study investigates whether, in these older persons, changes in satisfaction with their GP, on receiving improved integrated care, is related to their perceived health state.Using the Integrated Systematic Care for Older People (ISCOPE) trial (aimed at improving person- centered integrated care) this study compared changes in satisfaction with the GP in older persons (aged ≥75 years) with a high level of complex health problems on receiving integrated care, stratified for perceived health state at baseline. Satisfaction with the GP was registered on a 5-point Likert scale. Perceived health state was estimated with the Older Persons and Informal Caregivers Survey-Composite End Point (TOPICS-CEP) at baseline, stratified into 33% percentiles. Differences in satisfaction change between the intervention and usual care/control groups (overall and stratified for perceived health state) are presented by percentages of 'very satisfied' participants and improving or deteriorating 1 or more points on the Likert scale. At baseline, the intervention (n = 151) and control group (n = 603) were mainly female (75%) and living alone (62%); mean age was 83 years. Medical status, perceived health state and characteristics of participants were similar. Overall, at baseline 44.4% of respondents in the intervention group were 'very satisfied' compared with 37.1% at follow-up, (difference -7.3%). In the control group, 'very satisfied' at baseline was 32% and at follow up 29.2% (difference -2.8%). The p-value for this difference in change is 0.56. After stratification for TOPICS-CEP the results were the same. In older persons with a high level of complexity of health problems, implementation of person- centered integrated healthcare did not influence their satisfaction with the GP, also not among those with the highest or lowest perceived health state., Competing Interests: The authors have declared that no competing interests exist.

Dozens of monoclonal antibodies (mAbs) have been approved for clinical use, and hundreds more are under development. To support these developments and facilitate a personalized medicine approach, PET imaging and quantification of mAbs, after chelation with desferrioxamine B (DFO) and radiolabeling with 89 Zr, has become attractive. Also, the use of 89 Zr-mAbs in preclinical and clinical studies is expanding rapidly. Despite these rapid developments, 89 Zr radiolabeling is still performed manually. Therefore, we aimed to develop a simple, fully automated, good-manufacturing-practice (GMP)-compliant production procedure for the 89 Zr labeling of mAbs. Such procedures should increase the robustness and capacity of 89 Zr-mAb production while minimizing the radiation dose to the operator. Here, the procedures for fully automated 89 Zr-mAb production are described and applied to produce batches of 89 Zr-DFO- N -suc-cetuximab and 89 Zr-DFO- N -suc-rituximab suitable for clinical use. Both products had to meet the GMP-compliant quality standards with respect to yield, radiochemical purity, protein integrity, antigen binding, sterility, and endotoxin levels. Methods: Automated 89 Zr labeling of mAbs was developed on a Scintomics GRP 2V module and comprised the following steps: reagent transfer to the 89 Zr-containing reaction vial, mixing of the reagents followed by a 60-min reaction at room temperature to obtain optimal radiolabeling yields, and product purification using a PD-10 desalting column. Results: Radiochemical yields of 89 Zr-DFO- N -suc-cetuximab and 89 Zr-DFO- N -suc-rituximab were all more than 90% according to instant thin-layer chromatography. Isolated yields were 74.6% ± 2.0% and 62.6% ± 3.0% for 89 Zr-DFO- N -suc-cetuximab and 89 Zr-DFO- N -suc-rituximab, respectively, which are similar to isolated yields obtained using GMP protocols for manual 89 Zr labeling of mAbs. To meet the GMP-compliant quality standards, only the radiochemically pure fractions were collected from PD-10, resulting in a lower isolated yield than the radiochemical yield according to instant thin-layer chromatography. The radiochemical purity and protein integrity were more than 95% for both products, and the antigen binding was 95.6% ± 0.6% and 87.1% ± 2.2% for 89 Zr-DFO- N -suc-cetuximab and 89 Zr-DFO- N -suc-rituximab, respectively. The products were sterile, and the endotoxin levels were within acceptable limits, allowing future clinical production using this procedure. Conclusion: Procedures for fully automated GMP-compliant production of 89 Zr-mAbs were developed on a commercially available synthesis module, which also allows the GMP production of other radiolabeled mAbs., (© 2019 by the Society of Nuclear Medicine and Molecular Imaging.)

Two potent SP 1-7 peptidomimetics have been successfully radiolabeled via [ 11 C]CO 2 -fixation with excellent yields, purity, and molar activity. l-[ 11 C]SP 1-7 -peptidomimetic exhibited promising ex vivo biodistribution profile. Metabolite analysis showed that l-[ 11 C]SP 1-7 -peptidomimetic is stable in brain and spinal cord, whereas rapid metabolic degradation occurs in rat plasma. Metabolic stability can be significantly improved by substituting l-Phe for d-Phe, preserving 70% more of intact tracer and resulting in better brain and spinal cord tracer retention. Positron emission tomography (PET) scanning confirmed moderate brain (1.5 SUV; peak at 3 min) and spinal cord (1.0 SUV; peak at 10 min) uptake for l- and d-[ 11 C]SP 1-7 -peptidomimetic. A slight decrease in SUV value was observed after pretreatment with natural peptide SP 1-7 in spinal cord for l-[ 11 C]SP 1-7 -peptidomimetic. On the contrary, blocking using cold analogues of l- and d-[ 11 C]tracers did not reduce the tracers' brain and spinal cord exposure. In summary, PET scanning of l- and d-[ 11 C]SP 1-7 -peptidomimetics confirms rapid blood-brain barrier and blood-spinal-cord barrier penetration. Therefore, further validation of these two tracers targeting SP 1-7 is needed in order to define a new PET imaging target and select its most appropriate radiopharmaceutical.

Radiolabeled amino acids, their derivatives and peptides have a broad scope of application and can be used as receptor ligands, as well as enzyme substrates for many different diseases as radiopharmaceutical tracers. Over the past few decades, the application of molecular imaging techniques such as positron emission tomography (PET) has gained considerable importance and significance in diagnosis in today's advanced health care. Next to that, the availability of cyclotrons and state-of-the-art radiochemistry facilities has progressed the production of imaging agents enabling the preparation of many versatile PET radiotracers. Due to many favorable characteristics of radiolabeled amino acids and peptides, they can be used for tumor staging and monitoring the progress of therapy success, while aromatic amino acids can be employed as PET tracer to study neurological disorders. This review provides a comprehensive overview of radiosynthetic and enzymatic approaches towards carbon-11 amino acids, their analogues and peptides, with focus on stereoselective reactions, and reflects upon their clinical application.

Objective: Understanding patient satisfaction from the perspective of older adults is important to improve quality of their care. Since patient and care variables which can be influenced are of specific interest, this study examines the relation between patient satisfaction and the perceived doctor-patient relationship in older persons and their general practitioners (GPs)., Design: Cross-sectional survey., Subjects and Setting: Older persons (n = 653, median age 87 years; 69.4% female) living in 41 residential homes., Main Outcome Measures: Patient satisfaction (report mark) and perceived doctor-patient relationship (Leiden Perioperative care Patient Satisfaction questionnaire); relationships were examined by comparing medians and use of regression models., Results: The median satisfaction score was 8 (interquartile range 7.5-9; range 0-10) and doctor-patient relationship 65 (interquartile range 63-65; range 13-65). Higher satisfaction scores were related to higher scores on doctor-patient relationship (Jonckheere Terpstra test, p for trend <.001) independent of gender, age, duration of stay in the residential home, functional and clinical characteristics. Adjusted for these characteristics, per additional point for doctor-patient relationship, satisfaction increased with 0.103 points (β = 0.103, 95% CI 0.092-0.114; p < .001). In those with a 'low' doctor-patient relationship rating, the percentage awarding 'sufficient or good' to their GP for 'understanding about the personal situation' was 12%, 'receiving attention as an individual' 22%, treating the patient kindly 78%, and being polite 94%., Conclusion: In older persons, perceived doctor-patient relationship and patient satisfaction are related, irrespective of patient characteristics. GPs may improve patient satisfaction by focusing more on the affective aspects of the doctor-patient relationship. Key Points Examination of the perceived doctor-patient relationship as a variable might better accommodate patients' expectations and improve satisfaction with the provided primary care.

A thorough systematic literature review comparing care for the elderly provided by physicians and nurses with that provided by physicians alone finds a modest advantage for the first. The conclusion is that 'Physician substitution in healthcare for the aging population may achieve at least as good patient outcomes and process of care outcomes compared with care provided by physicians'. On closer inspection, the selected studies compare multidisciplinary care programmes including nursing staff with monodisciplinary physician care. The modest advantage found for the multidisciplinary programmes can be seen as support for the prevailing consensus that this is the way to go, but the conclusion that this is support for the substitution of physicians lacks evidence. Focus on cost-effectiveness and/or the wish to accentuate the important role of highly trained nursing experts in modern care for older people may have affected the interpretation of the data.

The oncometabolite 2-hydroxyglutarate (2-HG) is a signature biomarker in various cancers, where it accumulates as a result of mutations in isocitrate dehydrogenase (IDH). The metabolic source of 2-HG, in a wide variety of cancers, dictates both its generation and also potential therapeutic strategies, but this remains difficult to access in vivo. Here, utilizing patient-derived chondrosarcoma cells harboring endogenous mutations in IDH1 and IDH2, we report that 2-HG can be rapidly generated from glutamine in vitro. Then, using hyperpolarized magnetic resonance imaging (HP-MRI), we demonstrate that in vivo HP [1- 13 C] glutamine can be used to non-invasively measure glutamine-derived HP 2-HG production. This can be readily modulated utilizing a selective IDH1 inhibitor, opening the door to targeting glutamine-derived 2-HG therapeutically. Rapid rates of HP 2-HG generation in vivo further demonstrate that, in a context-dependent manner, glutamine can be a primary carbon source for 2-HG production in mutant IDH tumors., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The multitude of biologically active compounds requires the availability of a broad spectrum of radiolabeled synthons for the development of positron emission tomography (PET) tracers. The aim of this study was to synthesize 1-iodo-2-[ 11 C]methylpropane and 2-methyl-1-[ 11 C]propanol and investigate the use of these reagents in further radiosynthesis reactions. 2-Methyl-1-[ 11 C]propanol was obtained with an average radiochemical yield of 46 ± 6% d.c. and used with fluorobenzene as starting material. High conversion rates of 85 ± 4% d.c. could be observed with HPLC, but large precursor amounts (32 mg, 333 μmol) were needed. 1-Iodo-2-[ 11 C]methylpropane was synthesized with a radiochemical yield of 25 ± 7% d.c. and with a radiochemical purity of 78 ± 7% d.c. The labelling agent 1-iodo-2-[ 11 C]methylpropane was coupled to thiophenol, phenol and phenylmagnesium bromide. Average radiochemical conversions of 83% d.c. for thiophenol, 40% d.c. for phenol, and 60% d.c. for phenylmagnesium bromide were obtained. In addition, [ 11 C]2-methyl-1-propyl phenyl sulphide was isolated with a radiochemical yield of 5 ± 1% d.c. and a molar activity of 346 ± 113 GBq/μmol at the end of synthesis. Altogether, the syntheses of 1-iodo-2-[ 11 C]methylpropane and 2-methyl-1-[ 11 C]propanol were achieved and applied as proof of their applicability., (Copyright © 2017 John Wiley & Sons, Ltd.)

Positron emission tomography (PET) is an important driver for present day healthcare. Fluorine-18 is the most widely used radioisotope for PET imaging and a thorough overview of the available radiochemistry methodology is a prerequisite for selection of a synthetic approach for new fluorine-18 labelled PET tracers. These PET tracers can be synthesised either by late-stage radiofluorination, introducing fluorine-18 in the last step of the synthesis, or by a building block approach (also called modular build-up approach), introducing fluorine-18 in a fast and efficient manner in a building block, which is reacted further in one or multiple reaction steps to form the PET tracer. This review presents a comprehensive overview of the synthesis and application of fluorine-18 labelled building blocks since 2010.

Over the last decade kinase inhibitors have witnessed tremendous growth as anti-cancer drugs. Unfortunately, despite their promising clinical successes, a large portion of patients does not benefit from these targeted therapeutics. Vemurafenib is a serine/threonine kinase inhibitor approved for the treatment of melanomas specifically expressing the BRAFV600E mutation. The aim of this study was to develop vemurafenib as PET tracer to determine its potential for identification of tumors sensitive to vemurafenib treatment. Therefore, vemurafenib was labeled with carbon-11 and analyzed for its tumor targeting potential in melanoma xenografts Colo829 (BRAFV600E) and MeWo (BRAFwt) using autoradiography on tissue sections, in vitro tumor cell uptake studies and biodistribution studies in xenografted athymic nu/nu mice. [11C]vemurafenib was synthesized in 21 ± 4% yield (decay corrected, calculated from [11C]CO) in > 99% radiochemical purity and a specific activity of 55 ± 18 GBq/μmol. Similar binding of [11C]vemurafenib was shown during autoradiography and cellular uptake studies in both cell lines. Plasma metabolite analysis demonstrated > 95% intact [11C]vemurafenib in vivo at 45 minutes after injection, indicating excellent stability. Biodistribution studies confirmed the in vitro results, showing similar tumor-to-background ratios in both xenografts models. These preliminary results suggest that identification of BRAFV600E mutations in vivo using PET with [11C]vemurafenib will be challenging.

A rapid method for the synthesis of carbon-11 radiolabeled phenylalanine was developed using a chiral phase-transfer catalyst and a sub-nanomolar quantity of [ 11 C]benzyl iodide as a radio-precursor. Based on a reported synthesis of [ 11 C]benzyl iodide, a Schiff base precursor was evaluated for stereoselective [ 11 C]benzylation. Extensive and interactive screening of the precursor, catalyst, base, stirring and temperature was required to achieve high stereoinduction. The result is an efficient 5-step radiolabeling method to reliably synthesize l- or d-[ 11 C]phenylalanine with an excellent enantiomeric excess of >90% and almost quantitative radiochemical conversion of >95% (n > 5). Additionally, a phase-transfer catalyzed alkylation was utilized on the preparative scale using automated platform. The application resulted in high specific activity ranging from 85-135 GBq μmol -1 of the enantiomerically pure [ 11 C]phenylalanine, showing that the process is robust and amenable to broad use in PET.

Evaluation of the implementation of integrated care can differ from trial-based research due to complexity. Therefore, we examined whether a theory-based method for process description of implementation can contribute to improvement of evidence-based care. MOVIT, a Dutch project aimed at implementing integrated care for older vulnerable persons in residential care homes, was used as a case study. The project activities were defined according to implementation taxonomy and mapped in a matrix of theoretical levels and domains. Project activities mainly targeted professionals (both individual and group). A few activities targeted the organizational level, whereas none targeted the policy level, or the patient, or the "social, political, and legal" domains. However, the resulting changes in care delivery arrangement had consequences for professionals, patients, organizations, and the social, political, and legal domains. A structured process description of a pragmatic implementation project can help assess the fidelity and quality of the implementation, and identify relevant contextual factors for immediate adaptation and future research. The description showed that, in the MOVIT project, there was a discrepancy between the levels and domains targeted by the implementation activities and those influenced by the resulting changes in delivery arrangement. This could have influenced, in particular, the adoption and sustainability of the project.

Background: Integrated care for older persons with complex care needs is widely advocated. Particularly professionals and policy makers have positive expectations. Care outcome results are ambiguous. Receiver and provider satisfaction is relevant but still poorly understood., Methods: During implementation of integrated care in residential homes (The MOVIT project), we compared general satisfaction and satisfaction with specific aspects of General Practitioner (GP) care in older persons and GPs before (cohort I) and after at least 12 months of implementation (cohort II)., Results: The general satisfaction score for GP care given by older persons does not change (Cohort I (n = 762) mean score 8.0 (IQR:7.0-9.0) vs. Cohort II (n = 505) mean score 8.0 (IQR:7.0-8.0);P = 0.01). Expressions of general satisfaction in GPs do not show consistent change (Cohort I (n = 87) vs Cohort II (n = 66), percentage satisfied about; role as GP, 56% vs 67%;P = 0.194, ability to provide personal care, 60% vs 67%;P = 0.038, quality of care, 54% vs 62%;P = 0.316). Satisfaction in older persons about some specific aspects of care do show change; GP-patient relationship, points 61.6 vs 63.3;P = 0.001, willingness to talk about mistakes, score 3.47 vs 3.73;P = 0.001, information received about drugs, score 2.79 vs 2.46;P = 0.002. GPs also report changes in specific aspects: percentage satisfied about multidisciplinary meetings; occurrence, 21% vs 53%;P = <0.001, GP presence, 12% vs 41%;P = <0.001, and participation, 29% vs.51%;P = 0.046., Conclusion: General satisfaction about care received and provided shows no consistent change in older persons and GPs during the implementation of integrated care. Specific changes in satisfaction are found. These show an emphasis on inter-personal aspects in older persons and organizational aspects in GPs., Competing Interests: The authors have declared that no competing interests exist.

Introduction: Tyrosine kinase inhibitors (TKIs) are very attractive targeted drugs, although a large portion of patients remains unresponsive. PET imaging with EGFR targeting TKIs ([(11)C]erlotinib and [(18)F]afatinib) showed promise in identifying treatment sensitive tumors. The aim of this study was to synthesize two anti-angiogenic TKI tracers, [(11)C]axitinib and [(11)C]nintedanib, and to evaluate their potential for PET., Methods: Following successful tracer synthesis, biodistribution studies in VU-SCC-OE and FaDu xenograft bearing mice were performed. Furthermore, tracer stability studies in mice were performed employing (radio-)HPLC and LC-MS/MS techniques. For [(11)C]nintedanib an LC-MS/MS method was developed to detect the primary carboxylic acid metabolite, resulting from methylester cleavage, in plasma and tumors, because this metabolite is postulated to be important for nintedanib efficacy. LC-MS/MS was also explored to assess the metabolic fate of [(11)C]axitinib in vivo, since axitinib has an isomerizable double bond., Results: [(11)C]axitinib and [(11)C]nintedanib were successfully synthesized with 10.5±2.6% and 25.6±3.3% radiochemical yield (corrected for decay), respectively. Biodistribution studies only demonstrated tumor uptake of [(11)C]nintedanib in FaDu xenografts of 1.66±0.02% ID/g at 60min p.i. In vivo stability analysis of [(11)C]axitinib at 45min p.i. revealed the formation of predominantly non-polar metabolites (36.6±6.8% vs 47.1±8.4% of parent tracer and 16.3±2.1% of polar metabolites), while for [(11)C]nintedanib mostly polar metabolites were found (70.9±4.1 vs 26.7±3.9% of parent tracer and only 2.4±1.6 of a non-polar metabolites). No isomerization of [(11)C]axtinib was observed in vivo; however, a sulfoxide metabolite could be detected using LC-MS/MS. For [(11)C]nintedanib, LC-MS/MS revealed formation of the reported primary carboxylic acid metabolite when in vitro plasma incubations were performed, with large differences in plasmas from different species. In vivo metabolite analysis, however, did not demonstrate the presence of the carboxylic acid in plasma or tumor tissue., Conclusions: Reliable syntheses of [(11)C]axitinib and [(11)C]nintedanib were successfully developed. Tumor uptake was observed for [(11)C]nintedanib, albeit modest. The metabolic profiles of the tracers suggest that rapid metabolism is partly responsible for the modest tumor targeting observed., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Hyperpolarized magnetic resonance spectroscopy (HP MRS) using dynamic nuclear polarization (DNP) is a technique that has greatly enhanced the sensitivity of detecting (13)C nuclei. However, the HP MRS polarization decays in the liquid state according to the spin-lattice relaxation time (T1) of the nucleus. Sampling of the signal also destroys polarization, resulting in a limited temporal ability to observe biologically interesting reactions. In this study, we demonstrate that sampling hyperpolarized signals using a permanent magnet at 1 Tesla (1T) is a simple and cost-effective method to increase T1s without sacrificing signal-to-noise. Biologically-relevant information may be obtained with a permanent magnet using enzyme solutions and in whole cells. Of significance, our findings indicate that changes in pyruvate metabolism can also be quantified in a xenograft model at this field strength.

Positron emission tomography has increased the demand for new carbon-11 radiolabeled tracers and building blocks. A promising radiolabeling synthon is [(11) C]benzyl iodide ([(11) C]BnI), because the benzyl group is a widely present functionality in biologically active compounds. Unfortunately, synthesis of [(11) C]BnI has received little attention, resulting in limited application. Therefore, we investigated the synthesis in order to significantly improve, automate, and apply it for labeling of the dopamine D2 antagonist [(11) C]clebopride as a proof of concept. [(11) C]BnI was synthesized from [(11) C]CO2 via a Grignard reaction and purified prior the reaction with desbenzyl clebopride. According to a one-pot procedure, [(11) C]BnI was synthesized in 11 min from [(11) C]CO2 with high yield, purity, and specific activity, 52 ± 3% (end of the cyclotron bombardment), 95 ± 3%, and 123 ± 17 GBq/µmol (end of the synthesis), respectively. Changes in the [(11) C]BnI synthesis are reduced amounts of reagents, a lower temperature in the Grignard reaction, and the introduction of a solid-phase intermediate purification. [(11) C]Clebopride was synthesized within 28 min from [(11) C]CO2 in an isolated decay-corrected yield of 11 ± 3% (end of the cyclotron bombardment) with a purity of >98% and specific activity (SA) of 54 ± 4 GBq/µmol (n = 3) at the end of the synthesis. Conversion of [(11) C]BnI to product was 82 ± 11%. The reliable synthesis of [(11) C]BnI allows the broad application of this synthon in positron emission tomography radiopharmaceutical development., (Copyright © 2015 John Wiley & Sons, Ltd.)

Background: Tyrosine kinase inhibitors (TKIs) have experienced a tremendous boost in the last decade, where more than 15 small molecule TKIs have been approved by the FDA. Unfortunately, despite their promising clinical successes, a large portion of patients remain unresponsive to these targeted drugs. For non-small cell lung cancer (NSCLC), the effectiveness of TKIs is dependent on the mutational status of epidermal growth factor receptor (EGFR). The exon 19 deletion as well as the L858R point mutation lead to excellent sensitivity to TKIs such as erlotinib and gefitinib; however, despite initial good response, most patients invariably develop resistance against these first-generation reversible TKIs, e.g., via T790M point mutation. Second-generation TKIs that irreversibly bind to EGFR wild-type and mutant isoforms have therefore been developed and one of these candidates, afatinib, has now reached the market. Whether irreversible TKIs differ from reversible TKIs in their in vivo tumor-targeting properties is, however, not known and is the subject of the present study., Methods: Erlotinib was labeled with carbon-11 and afatinib with fluorine-18 without modifying the structure of these compounds. A preclinical positron emission tomography (PET) study was performed in mice bearing NSCLC xenografts with a representative panel of mutations: an EGFR-WT xenograft cell line (A549), an acquired treatment-resistant L858R/T790M mutant (H1975), and a treatment-sensitive exon 19 deleted mutant (HCC827). PET imaging was performed in these xenografts with both tracers. Additionally, the effect of drug efflux transporter permeability glycoprotein (P-gp) on the tumor uptake of tracers was explored by therapeutic blocking with tariquidar., Results: Both tracers only demonstrated selective tumor uptake in the HCC827 xenograft line (tumor-to-background ratio, [(11)C]erlotinib 1.9 ± 0.5 and [(18)F]afatinib 2.3 ± 0.4), thereby showing the ability to distinguish sensitizing mutations in vivo. No major differences were observed in the kinetics of the reversible and the irreversible tracers in each of the xenograft models. Under P-gp blocking conditions, no significant changes in tumor-to-background ratio were observed; however, [(18)F]afatinib demonstrated better tumor retention in all xenograft models., Conclusions: TKI-PET provides a method to image sensitizing mutations and can be a valuable tool to compare the distinguished targeting properties of TKIs in vivo.

Introduction: Afatinib is an irreversible ErbB family blocker that was approved for the treatment of EGFR mutated non-small cell lung cancer in 2013. Positron emission tomography (PET) with fluorine-18 labeled afatinib provides a means to obtain improved understanding of afatinib tumor disposition in vivo. PET imaging with [(18)F]afatinib may also provide a method to select treatment responsive patients. The aim of this study was to label afatinib with fluorine-18 and evaluate its potential as TKI-PET tracer in tumor bearing mice., Methods: A radiochemically novel coupling, using peptide coupling reagent BOP, was explored and optimized to synthesize [(18)F]afatinib, followed by a metabolite analysis and biodistribution studies in two clinically relevant lung cancer cell lines, xenografted in nude mice., Results: A reliable [(18)F]afatinib radiosynthesis was developed and the tracer could be produced in yields of 17.0 ± 2.5% calculated from [(18)F]F(-) and >98% purity. The identity of the product was confirmed by co-injection on HPLC with non-labeled afatinib. Metabolite analysis revealed a moderate rate of metabolism, with >80% intact tracer in plasma at 45 min p.i. Biodistribution studies revealed rapid tumor accumulation and good retention for a period of at least 2 hours, while background tissues showed rapid clearance of the tracer., Conclusion: We have developed a method to synthesize [(18)F]afatinib and related fluorine-18 labeled 4-anilinoquinazolines. [(18)F]Afatinib showed good stability in vivo, justifying further evaluation as a TKI-PET tracer., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Satisfaction is widely used to evaluate and direct delivery of medical care; a complicated relationship exists between patient satisfaction, morbidity and age. This study investigates the relationships between complexity of health problems and level of patient satisfaction of older persons with their general practitioner (GP) and practice., Methods and Findings: This study is embedded in the ISCOPE (Integrated Systematic Care for Older Persons) study. Enlisted patients aged ≥75 years from 59 practices received a written questionnaire to screen for complex health problems (somatic, functional, psychological and social). For 2664 randomly chosen respondents (median age 82 years; 68% female) information was collected on level of satisfaction (satisfied, neutral, dissatisfied) with their GP and general practice, and demographic and clinical characteristics including complexity of health problems. Of all participants, 4% was dissatisfied with their GP care, 59% neutral and 37% satisfied. Between these three categories no differences were observed in age, gender, country of birth or education level. The percentage of participants dissatisfied with their GP care increased from 0.4% in those with 0 problem domains to 8% in those with 4 domains, i.e. having complex health problems (p<0.001). Per additional health domain with problems, the risk of being dissatisfied increased 1.7 times (95% CI 1.4-2.14; p<0.001). This was independent of age, gender, and demographic and clinical parameters (adjusted OR 1.4, 95% CI 1.1-1.8; p = 0.021)., Conclusion: In older persons, dissatisfaction with general practice is strongly correlated with rising complexity of health problems, independent of age, demographic and clinical parameters. It remains unclear whether complexity of health problems is a patient characteristic influencing the perception of care, or whether the care is unable to handle the demands of these patients. Prospective studies are needed to investigate the causal associations between care organization, patient characteristics, indicators of quality, and patient perceptions.

Introduction: Tyrosine kinase inhibitors (TKIs) like sorafenib are important anticancer therapeutics with thus far limited treatment response rates in cancer patients. Positron emission tomography (PET) could provide the means for selection of patients who might benefit from TKI treatment, if suitable PET tracers would be available. The aim of this study was to radiolabel sorafenib (1) with carbon-11 and to evaluate its potential as TKI-PET tracer in vivo., Methods: Synthetic methods were developed in which sorafenib was labeled at two different positions, followed by a metabolite analysis in rats and a PET imaging study in tumor-bearing mice., Results: [methyl-(11)C]-1 and [urea-(11)C]-1 were synthesized in yields of 59% and 53%, respectively, with a purity of >99%. The identity of the products was confirmed by coinjection on HPLC with reference sorafenib. In an in vivo metabolite analysis [(11)C]sorafenib proved to be stable. The percentage of intact product in blood-plasma after 45 min was 90% for [methyl-(11)C]-1 and 96% for [urea-(11)C]-1, respectively. Due to the more reliable synthesis, further research regarding PET imaging was performed with [methyl-(11)C]-1 in nude mice bearing FaDu (head and neck cancer), MDA-MB-231 (breast cancer) or RXF393 (renal cancer) xenografts. Highest tracer accumulation at a level of 2.52 ± 0.33%ID/g was observed in RXF393, a xenograft line extensively expressing the sorafenib target antigen Raf-1 as assessed by immunohistochemistry., Conclusion: In conclusion, we have synthesized [(11)C]sorafenib as PET tracer, which is stable in vivo and has the capability to be used as PET tracer for imaging in tumor-bearing mice., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Kinases present an attractive target for drug development, since they are involved in vital cellular processes and are implicated in a variety of diseases, such as cancer and diabetes. However, obtaining selectivity for a specific kinase over others is difficult since many current kinase inhibitors exclusively target the highly conserved kinase ATP binding domain. Previously, a microarray-based strategy to discover so-called bisubstrate-based inhibitors that target the more specific peptide binding groove in addition to the ATP binding site was described. One attractive feature of this strategy is the opportunity to tune the selectivity of these inhibitors by systematically varying components. In an extension to this previous work, this study explores the potential of this guided selectivity modulation, leading to a series of inhibitors with different selectivity profiles against highly homologous protein kinase C (PKC) isozymes. Of the inhibitors studied, most exhibited improved potency and selectivity compared with their constituent parts. Furthermore, the selectivity was found to be tunable either through modification of the pseudosubstrate peptide (peptide binding groove) or the ATP-competitive part (ATP binding site). In a number of cases, the selectivity of the construct could be predicted from the initial peptide substrate profiling experiment. Since this strategy is applicable to all kinase sets, it could be used to rapidly develop uniquely selective inhibitors., (Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The discovery and increased understanding of tumor targets has led to the development and approval of 12 small molecule tyrosine kinase inhibitors (TKIs). Despite tremendous efforts in TKI development, treatment efficacies with these therapeutics are still too low and improvements require a personalized medicine approach. Positron emission tomography (PET) with radiolabeled TKIs (TKI-PET) is a tracking, quantification and imaging method, which provides a unique understanding of the behavior of these drugs in vivo and of the interaction with their target(s). In this article we provide an overview of tracer synthesis and development because each TKI requires a tailor made approach. Moreover, we describe current preclinical work and the first proof-of-principle clinical studies on the application of TKI-PET, illustrating the potential of this approach for improving therapy efficacy and personalized cancer treatment., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

During the last decade, the discovery of critical tumor targets has boosted the design of targeted therapeutic agents with monoclonal antibodies (mAbs) and tyrosine kinase inhibitors (TKIs) receiving most of the attention. Immuno-positron emission tomography (immuno-PET) and TKI-PET, the in vivo tracking and quantification of mAbs and TKIs biodistribution with PET, are exciting novel options for better understanding of the in vivo behavior and efficacy of these targeted drugs in individual patients and for more efficient drug development. Very recently, current good manufacturing practice compliant procedures for labeling of mAbs with positron emitters have been described, as well as the preparation of some radiolabeled TKIs, while the first proof of principle studies has been performed in patients. In this review, technical developments in immuno-PET and TKI-PET are described, and their clinical potential is discussed. An overview is provided for the most appealing preclinical immuno-PET and TKI-PET studies, as well as the first clinical achievements with these emerging technologies.

Efficient strategies for the introduction of arginine residues featuring acetylene or azide moieties in their side chains are described. The substituents are introduced in a way that maintains the basicity of the guanidine moiety. The methodology can be used e.g. for non-invasive labeling of arginine-containing peptides. Its applicability is demonstrated by the introduction of 'click' handles into a Protein Kinase C (PKC) pseudosubstrate peptide, and the subsequent preparation and evaluation of a novel bisubstrate-based inhibitor based on such a peptide.