11C-methyl-L-methionine PET measuring parameters for the diagnosis of tumour progression against radiation-induced changes in brain metastases.

OBJECTIVES: Radiation-induced changes (RIC) secondary to focal radiotherapy can imitate tumour progression in brain metastases and make follow-up clinical decision making unreliable. 11C-methyl-L-methionine-PET (MET-PET) is widely used for the diagnosis of RIC in brain metastases, but minimal literature exists regarding the optimum PET measuring parameter to be used. We analysed the diagnostic performance of different MET-PET measuring parameters in distinguishing between RIC and tumour progression in a retrospective cohort of brain metastasis patients. METHODS: 26 patients with 31 metastatic lesions were included on the basis of having undergone a PET scan due to radiological uncertainty of disease progression. The PET images were analysed and methionine uptake quantified using standardised-uptake-values (SUV) and tumour-to-normal tissue (T/N) ratios, generated as SUVmean, SUVmax, SUVpeak, T/Nmean, T/Nmax-mean and T/Npeak-mean. Metabolic-tumour-volume and total-lesion methionine metabolism were also computed. A definitive diagnosis of either RIC or tumour progression was established by clinicoradiological follow-up of least 4 months subsequent to the investigative PET scan. RESULTS: All MET-PET parameters except metabolic-tumour-volume showed statistically significant differences between tumour progression and lesions with RIC. Receiver-operating-characteristic curve and area-under the-curve analysis demonstrated the highest value of 0.834 for SUVmax with a corresponding optimum threshold of 3.29. This associated with sensitivity, specificity, positive predictive and negative predictive values of 78.57, 70.59%, 74.32 and 75.25% respectively. CONCLUSIONS: MET-PET is a useful modality for the diagnosis of RIC in brain metastases. SUVmax was the PET parameter with the greatest diagnostic performance. ADVANCES IN KNOWLEDGE: More robust comparisons between SUVmax and SUVpeak could enhance follow-up treatment planning.

Determination of brain tumor recurrence using 11 C-methionine positron emission tomography after radiotherapy.

We conducted a prospective multicenter trial to compare the usefulness of 11 C-methionine (MET) and 18 F-fluorodeoxyglucose (FDG) positron emission tomography (PET) for identifying tumor recurrence. Patients with clinically suspected tumor recurrence after radiotherapy underwent both 11 C-MET and 18 F-FDG PET. When a lesion showed a visually detected uptake of either tracer, it was surgically resected for histopathological analysis. Patients with a lesion negative to both tracers were revaluated by magnetic resonance imaging (MRI) at 3 months after the PET studies. The primary outcome measure was the sensitivity of each tracer in cases with histopathologically confirmed recurrence, as determined by the McNemar test. Sixty-one cases were enrolled, and 56 cases could be evaluated. The 38 cases where the lesions showed uptake of either 11 C-MET or 18 F-FDG underwent surgery; 32 of these cases were confirmed to be subject to recurrence. Eighteen cases where the lesions showed uptake of neither tracer received follow-up MRI; the lesion size increased in one of these cases. Among the cases with histologically confirmed recurrence, the sensitivities of 11 C-MET PET and 18 F-FDG PET were 0.97 (32/33, 95% confidence interval [CI]: 0.85-0.99) and 0.48 (16/33, 95% CI: 0.33-0.65), respectively, and the difference was statistically significant (P < .0001). The diagnostic accuracy of 11 C-MET PET was significantly better than that of 18 F-FDG PET (87.5% vs. 69.6%, P = .033). No examination-related adverse events were observed. The results of the study demonstrated that 11 C-MET PET was superior to 18 F-FDG PET for discriminating between tumor recurrence and radiation-induced necrosis.

Frequency and Characteristics of Nodal and Deltoid FDG and 11C-Choline Uptake on PET Performed After COVID-19 Vaccination.

BACKGROUND. COVID-19 vaccination may trigger reactive lymphadenopathy, confounding imaging interpretation. There has been limited systematic analysis of PET findings after COVID-19 vaccination. OBJECTIVE. The purpose of this study was to evaluate the frequency and characteristics of abnormal FDG and 11C-choline uptake on PET performed after COVID-19 vaccination. METHODS. This retrospective study included 67 patients (43 men and 24 women; mean [± SD] age, 75.6 ± 9.2 years) who underwent PET examination between December 14, 2020, and March 10, 2021, after COVID-19 vaccination and who had undergone prevaccination PET examination without visible axillary node uptake. A total of 52 patients received the BNT162b2 mRNA COVID-19 vaccine (Pfizer-BioNTech; hereafter referred to as the Pfizer-BioNTech vaccine), and 15 received the SARS-CoV-2 mRNA-1273 vaccine (Moderna; hereafter referred to as the Moderna vaccine). Sixty-six of the patients underwent PET/CT, and one underwent PET/MRI. Fifty-four PET examinations used FDG, and 13 used 11C-choline. PET was performed a median of 13 and 10 days after vaccination for patients who had received one (n = 44) and two (n = 23) vaccine doses, respectively. Two nuclear medicine physicians independently reviewed images and were blinded to injection laterality and the number of days since vaccination. Lymph node or deltoid SUVmax greater than the blood pool SUVmax was considered positive. Interreader agreement was assessed, and the measurements made by the more experienced physician were used for subsequent analysis. RESULTS. Positive axillary lymph node uptake was observed in 10.4% (7/67) of patients (7.4% [4/54] of FDG examinations and 23.1% [3/13] of 11C-choline examinations); of the patients with positive axillary lymph nodes, four had received the Pfizer vaccine, and three had received the Moderna vaccine. Injection laterality was documented for five of seven patients with positive axillary lymph nodes and was ipsilateral to the positive node in all five patients. PET was performed within 24 days of vaccination for all patients with a positive node. One patient showed extraaxillary lymph node uptake (ipsilateral supraclavicular uptake on FDG PET). Ipsilateral deltoid uptake was present in 14.5% (8/55) of patients with documented injection laterality, including 42.9% (3/7) of patients with positive axillary lymph nodes. Interreader agreement for SUV measurements (expressed as intraclass correlation coefficients) ranged from 0.600 to 0.988. CONCLUSION. Increased axillary lymph node or ipsilateral deltoid uptake is occasionally observed on FDG or 11C-choline PET performed after COVID-19 vaccination with the Pfizer-BioNTech or Moderna vaccine. CLINICAL IMPACT. Interpreting physicians should recognize characteristics of abnormal uptake on PET after COVID-19 vaccination to guide optimal follow-up management and reduce unnecessary biopsies.

In vivo tracking of 14C thymidine labeled mesenchymal stem cells using ultra-sensitive accelerator mass spectrometry.

Despite the tremendous advancements made in cell tracking, in vivo imaging and volumetric analysis, it remains difficult to accurately quantify the number of infused cells following stem cell therapy, especially at the single cell level, mainly due to the sensitivity of cells. In this study, we demonstrate the utility of both liquid scintillator counter (LSC) and accelerator mass spectrometry (AMS) in investigating the distribution and quantification of radioisotope labeled adipocyte derived mesenchymal stem cells (AD-MSCs) at the single cell level after intravenous (IV) transplantation. We first show the incorporation of 14C-thymidine (5 nCi/ml, 24.2 ng/ml) into AD-MSCs without affecting key biological characteristics. These cells were then utilized to track and quantify the distribution of AD-MSCs delivered through the tail vein by AMS, revealing the number of AD-MSCs existing within different organs per mg and per organ at different time points. Notably, the results show that this highly sensitive approach can quantify one cell per mg which effectively means that AD-MSCs can be detected in various tissues at the single cell level. While the significance of these cells is yet to be elucidated, we show that it is possible to accurately depict the pattern of distribution and quantify AD-MSCs in living tissue. This approach can serve to incrementally build profiles of biodistribution for stem cells such as MSCs which is essential for both research and therapeutic purposes.

Functional imaging of adrenal cortex. / Estudios de imagen funcional de la corteza adrenal.

The rising number of high-resolution imaging scans has increased the adrenal lesions detection, which require a differential diagnosis. Currently, the most commonly used scans are CT and MRI, but these are sometimes not very specific. In these cases, nuclear medicine scans with 131I-norcolesterol, 11C-metomidate and 18F-fludeoxyglucose help to differentiate benign vs. malignant lesions, to lateralize the involvement in hypersecretion disease, as well as to guide the therapeutic strategy in both unilateral and bilateral lesions.

Imaging niacin trafficking with positron emission tomography reveals in vivo monocarboxylate transporter distribution.

INTRODUCTION: A sufficient dietary intake of the vitamin niacin is essential for normal cellular function. Niacin is transported into the cells by the monocarboxylate transporters: sodium-dependent monocarboxylate transporter (SMCT1 and SMCT2) and monocarboxylate transporter (MCT1). Despite the importance of niacin in biological systems, surprisingly, its in vivo biodistribution and trafficking in living organisms has not been reported. The availability of niacin radiolabelled with the short-lived positron emitting radionuclide carbon-11 ([11C]niacin) would enable the quantitative in vivo study of this endogenous micronutrient trafficking using in vivo PET molecular imaging. METHODS: [11C]Niacin was synthesised via a simple one-step, one-pot reaction in a fully automated system using cyclotron-produced carbon dioxide ([11C]CO2) and 3-pyridineboronic acid ester via a copper-mediated reaction. [11C]Niacin was administered intravenously in healthy anaesthetised mice placed in a high-resolution nanoScan PET/CT scanner. To further characterize in vivo [11C]niacin distribution in vivo, mice were challenged with either niacin or AZD3965, a potent and selective MCT1 inhibitor. To examine niacin gastrointestinal absorption and body distribution in vivo, no-carrier-added (NCA) and carrier-added (CA) [11C]niacin formulations were administered orally. RESULTS: Total synthesis time including HPLC purification was 25 ± 1 min from end of [11C]CO2 delivery. [11C]Niacin was obtained with a decay corrected radiochemical yield of 17 ± 2%. We report a rapid radioactivity accumulation in the kidney, heart, eyes and liver of intravenously administered [11C]niacin which is consistent with the known in vivo SMCTs and MCT1 transporter tissue expression. Pre-administration of non-radioactive niacin decreased kidney-, heart-, ocular- and liver-uptake and increased urinary excretion of [11C]niacin. Pre-administration of AZD3965 selectively decreased [11C]niacin uptake in MCT1-expressing organs such as heart and retina. Following oral administration of NCA [11C]niacin, a high level of radioactivity accumulated in the intestines. CA abolished the intestinal accumulation of [11C]niacin resulting in a preferential distribution to all tissues expressing niacin transporters and the excretory organs. CONCLUSIONS: Here, we describe the efficient preparation of [11C]niacin as PET imaging agent for probing the trafficking of nutrient demand in healthy rodents by intravenous and oral administration, providing a translatable technique to enable the future exploration of niacin trafficking in humans and to assess its application as a research tool for metabolic disorders (dyslipidaemia) and cancer.

Imaging Biotin Trafficking In Vivo with Positron Emission Tomography.

The water-soluble vitamin biotin is essential for cellular growth, development, and well-being, but its absorption, distribution, metabolism, and excretion are poorly understood. This paper describes the radiolabeling of biotin with the positron emission tomography (PET) radionuclide carbon-11 ([11C]biotin) to enable the quantitative study of biotin trafficking in vivo. We show that intravenously administered [11C]biotin is quickly distributed to the liver, kidneys, retina, heart, and brain in rodents-consistent with the known expression of the biotin transporter-and there is a surprising accumulation in the brown adipose tissue (BAT). Orally administered [11C]biotin was rapidly absorbed in the small intestine and swiftly distributed to the same organs. Preadministration of nonradioactive biotin inhibited organ uptake and increased excretion. [11C]Biotin PET imaging therefore provides a dynamic in vivo map of transporter-mediated biotin trafficking in healthy rodents. This technique will enable the exploration of biotin trafficking in humans and its use as a research tool for diagnostic imaging of obesity/diabetes, bacterial infection, and cancer.

Methods to Enhance the Metabolic Stability of Peptide-Based PET Radiopharmaceuticals.

The high affinity and specificity of peptides towards biological targets, in addition to their favorable pharmacological properties, has encouraged the development of many peptide-based pharmaceuticals, including peptide-based positron emission tomography (PET) radiopharmaceuticals. However, the poor in vivo stability of unmodified peptides against proteolysis is a major challenge that must be overcome, as it can result in an impractically short in vivo biological half-life and a subsequently poor bioavailability when used in imaging and therapeutic applications. Consequently, many biologically and pharmacologically interesting peptide-based drugs may never see application. A potential way to overcome this is using peptide analogues designed to mimic the pharmacophore of a native peptide while also containing unnatural modifications that act to maintain or improve the pharmacological properties. This review explores strategies that have been developed to increase the metabolic stability of peptide-based pharmaceuticals. It includes modifications of the C- and/or N-termini, introduction of d- or other unnatural amino acids, backbone modification, PEGylation and alkyl chain incorporation, cyclization and peptide bond substitution, and where those strategies have been, or could be, applied to PET peptide-based radiopharmaceuticals.

Metformin is distributed to tumor tissue in breast cancer patients in vivo: A 11C-metformin PET/CT study.

PURPOSE: Epidemiological studies and randomized clinical trials suggest that the antidiabetic drug, metformin, may have anti-neoplastic effects. The mechanism that mediates these beneficial effects has been suggested to involve direct action on cancer cells, but this will require distribution of metformin in tumor tissue. The present study was designed to investigate metformin distribution in vivo in breast and liver tissue in breast cancer patients. METHODS: Seven patients recently diagnosed with ductal carcinoma were recruited. Using PET/CT, tissue distribution of metformin was determined in vivo for 90 min after injection of a carbon-11-labeled metformin tracer. After surgery, tumor tissue was investigated for gene expression levels of metformin transporter proteins. RESULTS: Tumor tissue displayed a distinct uptake of metformin compared to normal breast tissue AUC0-90 min (75.4 ± 5.5 vs 42.3 ± 6.3) g/ml*min (p = 0.01). Maximal concentration in tumor was at 1 min where it reached approximately 30% of the activity in the liver. The metformin transporter protein with the highest gene expression in tumor tissue was multidrug and toxin extrusion 1 (MATE 1) followed by plasma membrane monoamine transporter (PMAT). CONCLUSION: This study confirms that metformin is transported into tumor tissue in women with breast cancer. This finding support that metformin may have direct anti-neoplastic effects on tumor cells in breast cancer patients. However, distribution of metformin in tumor tissue is markedly lower than in liver, an established metformin target tissue.

Assessing the Activity of Multidrug Resistance-Associated Protein 1 at the Lung Epithelial Barrier.

Multidrug resistance-associated protein 1 (adenosine triphosphate-binding cassette subfamily C member 1 [ABCC1]) is abundantly expressed at the lung epithelial barrier, where it may influence the pulmonary disposition of inhaled drugs and contribute to variability in therapeutic response. The aim of this study was to assess the impact of ABCC1 on the pulmonary disposition of 6-bromo-7-11C-methylpurine (11C-BMP), a prodrug radiotracer that is intracellularly conjugated with glutathione to form the ABCC1 substrate S-(6-(7-11C-methylpurinyl))glutathione (11C-MPG). Methods: Groups of Abcc1(-/-) rats, wild-type rats pretreated with the ABCC1 inhibitor MK571, and wild-type control rats underwent dynamic PET scans after administration of 11C-BMP intravenously or by intratracheal aerosolization. In vitro transport experiments were performed with unlabeled BMP on the human distal lung epithelial cell line NCI-H441. Results: The pulmonary kinetics of radioactivity significantly differed between wild-type and Abcc1(-/-) rats, but differences were more pronounced after intratracheal than after intravenous administration. After intravenous administration, lung exposure (area under the lung time-activity curve from 0 to 80 min after radiotracer administration [AUClung]) was 77% higher and the elimination slope of radioactivity washout from the lungs (kE,lung) was 70% lower in Abcc1(-/-) rats, whereas after intratracheal administration, AUClung was 352% higher and kE,lung was 86% lower in Abcc1(-/-) rats. Pretreatment with MK571 decreased kE,lung by 20% after intratracheal radiotracer administration. Intracellular accumulation of MPG in NCI-H441 cells was significantly higher and extracellular efflux was lower in the presence than in the absence of MK571. Conclusion: PET with pulmonary administered 11C-BMP can measure ABCC1 activity at the lung epithelial barrier and may be applicable in humans to assess the effects of disease, genetic polymorphisms, or concomitant drug intake on pulmonary ABCC1 activity.

PET Imaging of Phosphodiesterase-4 Identifies Affected Dysplastic Bone in McCune-Albright Syndrome, a Genetic Mosaic Disorder.

McCune-Albright syndrome (MAS) is a mosaic disorder arising from gain-of-function mutations in the GNAS gene, which encodes the 3',5'-cyclic adenosine monophosphate (cAMP) pathway-associated G-protein, Gsα. Clinical manifestations of MAS in a given individual, including fibrous dysplasia, are determined by the timing and location of the GNAS mutation during embryogenesis, the tissues involved, and the role of Gsα in the affected tissues. The Gsα mutation results in dysregulation of the cAMP signaling cascade, leading to upregulation of phosphodiesterase type 4 (PDE4), which catalyzes the hydrolysis of cAMP. Increased cAMP levels have been found in vitro in both animal models of fibrous dysplasia and in cultured cells from individuals with MAS but not in humans with fibrous dysplasia. PET imaging of PDE4 with 11C-(R)-rolipram has been used successfully to study the in vivo activity of the cAMP cascade. To date, it remains unknown whether fibrous dysplasia and other symptoms of MAS, including neuropsychiatric impairments, are associated with increased PDE4 activity in humans. Methods:11C-(R)-rolipram whole-body and brain PET scans were performed on 6 individuals with MAS (3 for brain scans and 6 for whole-body scans) and 9 healthy controls (7 for brain scans and 6 for whole-body scans). Results:11C-(R)-rolipram binding correlated with known locations of fibrous dysplasia in the periphery of individuals with MAS; no uptake was observed in the bones of healthy controls. In peripheral organs and the brain, no difference in 11C-(R)-rolipram uptake was noted between participants with MAS and healthy controls. Conclusion: This study is the first to find evidence for increased cAMP activity in areas of fibrous dysplasia in vivo. No differences in brain uptake between MAS participants and controls were detected-a finding that could be due to several reasons, including the limited anatomic resolution of PET. Nevertheless, the results confirm the usefulness of PET scans with 11C-(R)-rolipram to indirectly measure increased cAMP pathway activation in human disease.

11C-Labeled Pictilisib (GDC-0941) as a Molecular Tracer Targeting Phosphatidylinositol 3-Kinase (PI3K) for Breast Cancer Imaging.

Pictilisib (GDC-0941) is an inhibitor of phosphatidylinositol 3-kinase (PI3K), part of a signaling cascade involved in breast cancer development. The purpose of this study was to evaluate the pharmacokinetics of pictilisib noninvasively by radiolabeling it with 11C and to assess the usability of the resulting [11C]-pictilisib as a positron-emission tomography (PET) tracer to screen for pictilisib-sensitive tumors. In this study, pictilisib was radiolabeled with [11C]-methyl iodide to obtain 11C-methylated pictilisib ([11C]-pictilisib) using an automated synthesis module with a high radiolabeling yield. Considerably higher uptake ratios were observed in MCF-7 (PIK3CA mutation, pictilisib-sensitive) cells than those in MDA-MB-231 (PIK3CA wild-type, pictilisib-insensitive) cells at all evaluated time points, indicating good in vitro binding of [11C]-pictilisib. Dynamic micro-PET scans in mice and biodistribution results showed that [11C]-pictilisib was mainly excreted via the hepatobiliary tract into the intestines. MCF-7 xenografts could be clearly visualized on the static micro-PET scans, while MDA-MB-231 tumors could not. Biodistribution results of two xenograft models showed significantly higher uptake and tumor-to-muscle ratios in the MCF-7 xenografts than those in MDA-MB-231 xenografts, exhibiting high in vivo targeting specificity. In conclusion, [11C]-pictilisib was first successfully prepared, and it exhibited good potential to identify pictilisib-sensitive tumors noninvasively, which may have a great impact in the treatment of cancers with an overactive PI3K/Akt/mTOR signal pathway. However, the high activity in hepatobiliary system and intestines needs to be addressed.

Evaluation of [11C]KB631 as a PET tracer for in vivo visualisation of HDAC6 in B16.F10 melanoma.

INTRODUCTION: HDAC6, a structural and functional distinct member of the HDAC-family, shows great promise as a target to treat several cancers and neurodegenerative diseases. Several clinical trials are evaluating HDAC6 inhibitors in solid tumours and haematological malignancies, but so far no HDAC6 inhibitor has received marketing authorisation. The availability of an HDAC6-specific PET tracer can potentially aid in cancer diagnosis, select patients for HDAC6 inhibitor treatment and accelerate HDAC6 drug development. We have evaluated the HDAC6 PET tracer [11C]KB631, in vitro and in vivo in B16.F10 melanoma inoculated mice. METHODS: In vitro binding specificity was evaluated by autoradiography studies on rodent brain, B16.F10 melanoma and PC3 prostate carcinoma cryosections. Biodistribution and quantification of plasma radio-metabolites was determined in NMRI-mice in control conditions and after blocking with KB631, Ricolinostat and SAHA. Tracer tumour uptake was evaluated in B16.F10 melanoma inoculated C57BL/6 mice. RESULTS: In vitro autoradiography studies showed HDAC6-selective binding to rodent brain, B16.F10 melanoma and PC3 prostate carcinoma tissue slices. Tracer binding in several organs of interest could be partially blocked in NMRI-mice pre-treated with KB631, Ricolinostat or SAHA, indicating specific tracer binding. A biodistribution and 90-min dynamic µPET study on B16.F10 melanoma mice, pre-treated with vehicle or Ricolinostat (50 mg/kg), indicated HDAC6-specific tumour uptake. CONCLUSIONS: [11C]KB631 shows HDAC6-selective binding in mouse B16.F10 melanoma tumours in vitro and in vivo. [11C]KB631 PET can be used for in vivo investigation of the expression of HDAC6 in tumours. ADVANCES IN KNOWLEDGE: [11C]KB631 shows increased expression of HDAC6 in mouse B16.F10 melanoma tumours and can be used to visualise target engagement of HDAC6 inhibitors.

Subcutaneous adipose tissue free fatty acid uptake measured using positron emission tomography and adipose biopsies in humans.

Positron emission tomography (PET) radiopharmaceuticals can noninvasively measure free fatty acid (FFA) uptake into adipose tissue. We studied 29 volunteers to test whether abdominal and femoral subcutaneous adipose tissue FFA uptake measured using [1-11C]palmitate PET agrees with FFA storage rates measured using an intravenous bolus of [1-14C]palmitate and adipose biopsies. The dynamic left ventricular cavity PET images combined with blood sample radioactivity corrected for the 11CO2 content were used to create the blood time activity curve (TAC), and the constant (Ki) was determined using Patlak analysis of the TACs generated for regions of interest in abdominal subcutaneous fat. These data were used to calculate palmitate uptake rates in abdominal subcutaneous adipose tissue (µmol·kg-1·min-1). Immediately after the dynamic imaging, a static image of the thigh was taken to measure the standardized uptake value (SUV) in thigh adipose tissue, which was scaled to each participant's abdominal adipose tissue SUV to calculate thigh adipose palmitate uptake rates. Abdominal adipose palmitate uptake using PET [1-11C]palmitate was correlated with, but significantly (P < 0.001) greater than, FFA storage measured using [1-14C]palmitate and adipose biopsy. Thigh adipose palmitate measured using PET calculation was positively correlated (R2 = 0.44, P < 0.0001) with and not different from the biopsy approach. The relative differences between PET measured abdominal subcutaneous adipose tissue palmitate uptake and biopsy-measured palmitate storage were positively correlated (P = 0.03) with abdominal subcutaneous fat. We conclude that abdominal adipose tissue FFA uptake measured using PET does not equate to adipose FFA storage measured using biopsy techniques.

Comprehensive preclinical pharmacokinetic evaluations of trastuzumab deruxtecan (DS-8201a), a HER2-targeting antibody-drug conjugate, in cynomolgus monkeys.

Trastuzumab deruxtecan (DS-8201a) is an antibody-drug conjugate (ADC) composed of a monoclonal antibody targeting human epidermal growth factor receptor 2 (HER2) conjugated to a topoisomerase I inhibitor (DXd) at a drug-to-antibody ratio (DAR) of 7-8. Here, we examined the pharmacokinetic (PK) profiles of DS-8201a and DXd in cynomolgus monkeys, a cross-reactive species. Following intravenous (iv) administration of DS-8201a, the linker was stable in plasma, and systemic DXd exposure was low. DXd was rapidly cleared following iv dosing. Biodistribution studies revealed that intact DS-8201a was present mostly in the blood without tissue-specific retention. The major pathway of excretion for DXd was the faecal route following iv administration of radiolabelled DS-8201a. The only detectable metabolite in the urine and faeces was unmetabolized DXd. DXd is a substrate of organic anion transporting polypeptides, P-gp, and breast cancer resistance protein. In conclusion, the stable linker in circulation and the high clearance of DXd upon release resulted in the low systemic exposure to DXd. Furthermore, the minimal tissue-specific retention and rapid excretion of DXd into faeces as its unmetabolized form with potentially limited impact on drug - drug interaction as a victim were also critical elements of the PK profile of DS-8201a.

Investigation of disposition for TAK-448, a synthetic peptide of kisspeptin analog, in rats and dogs using the radiolabeled TAK-448 suitable for pharmacokinetic study.

Disposition of 2-(N-acetyl-d-tyrosyl-trans-4-hydroxy-l-prolyl-l-asparaginyl-l-threonyl-l-phenylalanyl) hydrazinocarbonyl-L-leucyl-Nω-methyl-l-arginyl-l-tryptophanamide monoacetate (TAK-448, RVT-602), a synthetic kisspeptin analog, was investigated after parenteral dosing of radiolabeled TAK-448 ([d-Tyr-14C]TAK-448) to rats and dogs, and it was confirmed if the radiolabeling position at d-Tyr was eligible for assessment of in vivo disposition. Dosed radioactivity was rapidly and well absorbed after subcutaneous administration and an appreciable amount of unchanged TAK-448 (TAK-448F) and a hydrolyzed metabolite, M-I, were detected in the plasma of rats and dogs. After intravenous administration of [d-Tyr-14C]TAK-448 to rats, the radioactivity widely distributed to tissues with relatively higher concentrations in kidney and urinary bladder. The radioactivity was decreased rapidly from the tissues. After subcutaneous administration of [d-Tyr-14C]TAK-448 to rats and dogs, the dosed radioactivity was almost completely recovered by 48 and 72 h in rats and dogs, respectively, and most of the radioactivity was excreted in urine after extensive metabolism in the two species. These results suggest that TAK-448 has an acceptable pharmacokinetic profile for clinical evaluation and development, and demonstrate that the synthesized [D-Tyr-14C]TAK-448 used in this study represents a favorable labeling position to evaluate disposition properties of this compound.

Dynamic 11C-Choline PET / CT for the primary diagnosis of prostate cancer

ABSTRACT Objectives: To test the ability of dynamic 11C-PET / CT to discriminate cancerous tissue from background tissue in patients with localized prostate cancer. Materials and Methods: Twenty-four consecutive patients with prostate cancer were prospectively evaluated with dynamic 11C-choline PET / CT prior to radical prostatectomy. The PET / CT scan was divided into 18 sequences of 5 seconds each, followed by 9 sequences of 60 seconds each. Whole-mount sections of harvested prostates served as reference standards. Volumes of interest were positioned on the dynamic PET / CT images and the following quantitative variables were calculated: perfusion coefficient (K1), washout constant (K2), area under the curve (AUC) at 175 and 630 seconds, and average and maximum standardized uptake values (SUVavg, and SUVmax). Wilcoxon signed-ranks test was used to compare benign and cancerous areas of the prostate. Results: Areas of cancerous tissue were characterized by higher SUVavg and SUVmax than areas of benign tissue (3.67 ± 2.7 vs. 2.08 ± 1.3 and 5.91 ± 4.4 vs. 3.71 ± 3.7, respectively, P < 0.001), in addition to a higher K1 (0.95 ± 0.58 vs. 0.43 ± 0.24, P < 0.001) and greater cumulative tracer uptake, represented by the AUC at 175 and 630 seconds (P <0.001). No associations were found between dynamic parameters and preoperative prostate specific antigen level or Gleason score. Conclusions: In this pilot study, 11C-choline PET / CT demonstrated increased tracer uptake with higher values of static and dynamic parameters in areas of prostate cancer compared to areas of benign tissue. Larger studies are warranted to validate these results and examine the potential applicability of 11C-choline dynamic PET / CT for the diagnosis of prostate cancer.

Dynamic 11C-Choline PET / CT for the primary diagnosis of prostate cancer.

OBJECTIVES: To test the ability of dynamic 11C-PET / CT to discriminate cancerous tissue from background tissue in patients with localized prostate cancer. MATERIALS AND METHODS: Twenty-four consecutive patients with prostate cancer were prospectively evaluated with dynamic 11C-choline PET / CT prior to radical prostatectomy. The PET / CT scan was divided into 18 sequences of 5 seconds each, followed by 9 sequences of 60 seconds each. Whole-mount sections of harvested prostates served as reference standards. Volumes of interest were positioned on the dynamic PET / CT images and the following quantitative variables were calculated: perfusion coefficient (K1), washout constant (K2), area under the curve (AUC) at 175 and 630 seconds, and average and maximum standardized uptake values (SUVavg, and SUVmax). Wilcoxon signed-ranks test was used to compare benign and cancerous areas of the prostate. RESULTS: Areas of cancerous tissue were characterized by higher SUVavg and SUVmax than areas of benign tissue (3.67 ± 2.7 vs. 2.08 ± 1.3 and 5.91 ± 4.4 vs. 3.71 ± 3.7, respectively, P < 0.001), in addition to a higher K1 (0.95 ± 0.58 vs. 0.43 ± 0.24, P < 0.001) and greater cumulative tracer uptake, represented by the AUC at 175 and 630 seconds (P <0.001). No associations were found between dynamic parameters and preoperative prostate specific antigen level or Gleason score. CONCLUSIONS: In this pilot study, 11C-choline PET / CT demonstrated increased tracer uptake with higher values of static and dynamic parameters in areas of prostate cancer compared to areas of benign tissue. Larger studies are warranted to validate these results and examine the potential applicability of 11C-choline dynamic PET / CT for the diagnosis of prostate cancer.

Positron Emission Tomography Imaging of Lesions pH Using 11C-Labeled Bicarbonate.

OBJECTIVES: As acid-base imbalance is involved in many pathological processes, the capability to image tissue pH alterations in the clinic could offer new ways to detect disease and respond to treatment. In this study, the authors show that tissue pH can be imaged in vivo with 11C-labeled bicarbonate (H11CO3-) buffer and positron emission tomography (PET). METHODS: H11CO3- was produced by on-column NaOH adsorption. Biodistribution of H11CO3- in normal mice was determined. In addition, uptake studies and inhibition experiments of H11CO3- in the S180 fibrosarcoma-bearing mice and the inflammatory mice were investigated with PET imaging. The tumor and inflammatory interstitial pH was measured by a needle pH microelectrode. RESULTS: PET imaging demonstrated the high uptake of H11CO3- in mice tumor tissues and inflammatory tissues, which showed that the average tumor or inflammatory interstitial pH was significantly lower than the surrounding tissue. Administration of sodium bicarbonate in the drinking water increased the measured tumor pH, while the uptake of H11CO3- in mice model tissues had no change. Similarly, administration with ammonium chloride (NH4Cl) decreased the pH, whereas the unchanged uptake of H11CO3- in mice model tissues was also found. However, after administration of acetazolamide, the low uptake of H11CO3- in mice model tissues was observed. CONCLUSIONS: H11CO3- solution is an endogenous bicarbonate buffer tracer that can be injected into patients without toxicity. H11CO3- PET can be used clinically to image pathological processes that are associated with acid-base imbalance, such as cancer and inflammation.

A study of the focal adhesion kinase inhibitor GSK2256098 in patients with recurrent glioblastoma with evaluation of tumor penetration of [11C]GSK2256098.

Background: GSK2256098 is a novel oral focal adhesion kinase (FAK) inhibitor. Preclinical studies demonstrate growth inhibition in glioblastoma cell lines. However, rodent studies indicate limited blood-brain barrier (BBB) penetration. In this expansion cohort within a phase I study, the safety, tolerability, pharmacokinetics (PK), and clinical activity of GSK2256098 were evaluated in patients with recurrent glioblastoma. Biodistribution and kinetics of [11C]GSK2256098 were assessed in a substudy using positron-emission tomography (PET). Methods: Patients were treated with GSK2256098 until disease progression or withdrawal due to adverse events (AEs). Serial PK samples were collected on day 1. On a single day between days 9 and 20, patients received a microdose of intravenous [11C]GSK2256098 and were scanned with PET over 90 minutes with parallel PK sample collection. Response was assessed by MRI every 6 weeks. Results: Thirteen patients were treated in 3 dose cohorts (1000 mg, 750 mg, 500 mg; all dosed twice daily). The maximum tolerated dose was 1000 mg twice daily. Dose-limiting toxicities were related to cerebral edema. Treatment-related AEs (>25%) were diarrhea, fatigue, and nausea. Eight patients participated in the PET substudy, with [11C]GSK2256098 VT (volume of distribution) estimates of 0.9 in tumor tissue, 0.5 in surrounding T2 enhancing areas, and 0.4 in normal brain. Best response of stable disease was observed in 3 patients, including 1 patient on treatment for 11.3 months. Conclusions: GSK2256098 was tolerable in patients with relapsed glioblastoma. GSK2256098 crossed the BBB at low levels into normal brain, but at markedly higher levels into tumor, consistent with tumor-associated BBB disruption. Additional clinical trials of GSK2256098 are ongoing.