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Purpose: Glucagon-like peptide-1 receptor (GLP-1R) is a molecular target for imaging of pancreatic beta cells. We compared the ability of [Nle super(14),Lys super(40)( Ahx-NODAGA- super(64)Cu)NH sub(2)]-exendin-4 ([ super(64)Cu]NODAGA-exendin-4) and [Nle super(14),Lys super(40)( Ahx-NODAGA- super(68)Ga)NH sub(2)]-exendin-4 ([ super(68)Ga]NODAGA-exendin-4) to detect native pancreatic islets in rodents. Procedures: The stability, lipophilicity and affinity of the radiotracers to the GLP-1R were determined in vitro. The biodistribution of the tracers was assessed using autoradiography, ex vivo biodistribution and PET imaging. Estimates for human radiation dosimetry were calculated. Results: We found GLP-1R-specific labelling of pancreatic islets. However, the pancreas could not be visualised in PET images. The highest uptake of the tracers was observed in the kidneys. Effective dose estimates for [ super(64)Cu]NODAGA-exendin-4 and [ super(68)Ga]NODAGA-exendin-4 were 0.144 and 0.012 mSv/MBq, respectively. Conclusion: [ super(64)Cu]NODAGA-exendin-4 might be more effective for labelling islets than [ super(68)Ga]NODAGA-exendin-4. This is probably due to the lower specific radioactivity of [ super(68)Ga]NODAGA-exendin-4 compared to [ super(64)Cu]NODAGA-exendin-4. The radiation dose in the kidneys may limit the use of [ super(64)Cu]NODAGA-exendin-4 as a clinical tracer.

(E)-3-(pyridin-2-ylethynyl)cyclohex-2-enone O-2-(2-(18)F-fluoroethoxy)ethyl oxime, ([(18)F]-FDEGPECO), a novel high affinity radioligand for the metabotropic glutamate receptor subtype 5 (mGluR5) was assessed for its potential as a PET imaging agent. In vitro autoradiography on rat brain slices resulted in a heterogeneous and displaceable binding to mGluR5-rich brain regions. [(18)F]-FDEGPECO showed high stability in rat plasma and brain homogenate as well as in human plasma and microsomes. Good blood-brain barrier passage was predicted from an in vitro transport assay with P-glycoprotein-transfected hMDR1-MDCK cells. In vivo PET imaging on rats revealed specific uptake of radioactivity in the mGluR5-rich brain regions such as hippocampus, striatum and cortex while the cerebellum, a region with low mGluR5-expression, showed negligible uptake. Blockade experiments by co-injection of [(18)F]-FDEGPECO and M-MPEP (6mg/kg), an antagonist for mGluR5, reduced the level of radioactivity in mGluR5-regions to that of the cerebellum, pointing to an effective blockade of specifically bound [(18)F]-FDEGPECO. Postmortem biodistribution studies at 15min p.i. confirmed the distribution pattern observed in PET. HPLC analysis of rat brain extracts indicated that 98.5% and 91% of the total radioactivity were parent compound at 5min and 17min p.i., respectively. Taken together, the high affinity and the high in vivo specificity of [(18)F]-FDEGPECO for mGluR5 in the rat brain as well as the lack of in vivo defluorination make this new [(18)F]-labeled ABP688 derivative a suitable ligand for the preclinical PET imaging of mGluR5. These favorable characteristics warrant further evaluation in humans.(E)-3-(pyridin-2-ylethynyl)cyclohex-2-enone O-2-(2-(18)F-fluoroethoxy)ethyl oxime, ([(18)F]-FDEGPECO), a novel high affinity radioligand for the metabotropic glutamate receptor subtype 5 (mGluR5) was assessed for its potential as a PET imaging agent. In vitro autoradiography on rat brain slices resulted in a heterogeneous and displaceable binding to mGluR5-rich brain regions. [(18)F]-FDEGPECO showed high stability in rat plasma and brain homogenate as well as in human plasma and microsomes. Good blood-brain barrier passage was predicted from an in vitro transport assay with P-glycoprotein-transfected hMDR1-MDCK cells. In vivo PET imaging on rats revealed specific uptake of radioactivity in the mGluR5-rich brain regions such as hippocampus, striatum and cortex while the cerebellum, a region with low mGluR5-expression, showed negligible uptake. Blockade experiments by co-injection of [(18)F]-FDEGPECO and M-MPEP (6mg/kg), an antagonist for mGluR5, reduced the level of radioactivity in mGluR5-regions to that of the cerebellum, pointing to an effective blockade of specifically bound [(18)F]-FDEGPECO. Postmortem biodistribution studies at 15min p.i. confirmed the distribution pattern observed in PET. HPLC analysis of rat brain extracts indicated that 98.5% and 91% of the total radioactivity were parent compound at 5min and 17min p.i., respectively. Taken together, the high affinity and the high in vivo specificity of [(18)F]-FDEGPECO for mGluR5 in the rat brain as well as the lack of in vivo defluorination make this new [(18)F]-labeled ABP688 derivative a suitable ligand for the preclinical PET imaging of mGluR5. These favorable characteristics warrant further evaluation in humans.

The use of radiolabeled drug compounds offers the most efficient way to quantify the amount of drug and/or drug-derived metabolites in biological samples. Autoradiography is a technique using X- ray film, phosphor imaging plates, beta imaging systems, or photo-nuclear emulsion to visualize molecules or fragments of molecules that have been radioactively labeled, and it has been used to quantify and localize drugs in tissues and cells for decades. Quantitative whole-body autoradiography or autoradioluminography (QWBA) using phosphor imaging technology has revolutionized the conduct of drug distribution studies by providing high resolution images of the spatial distribution and matching tissue concentrations of drug-related radioactivity throughout the body of laboratory animals. This provides tissue-specific pharmacokinetic (PK) compartmental analysis which has been useful in toxicology, pharmacology, and drug disposition/patterns, and to predict human exposure to drugs and metabolites, and also radioactivity, when a human radiolabeled drug study is necessary. Microautoradiography (MARG) is another autoradiographic technique that qualitatively resolves the localization of radiolabeled compounds to the cellular level in a histological preparation. There are several examples in the literature of investigators attempting to obtain drug concentration data from MARG samples; however, there are technical issues which make that problematic. These issues will be discussed. This review will present a synopsis of both techniques and examples of how they have been used for drug research in recent years.

A single dose of psilocybin, a psychedelic and serotonin 2A receptor (5-HT2AR) agonist, may be associated with antidepressant effects. The mechanism behind its antidepressive action is unknown but could be linked to increased synaptogenesis and down-regulation of cerebral 5-HT2AR. Here, we investigate if a single psychedelic dose of psilocybin changes synaptic vesicle protein 2A (SV2A) and 5-HT2AR density in the pig brain. Twenty-four awake pigs received either 0.08 mg/kg psilocybin or saline intravenously. Twelve pigs (n = 6/intervention) were euthanized one day post-injection, while the remaining twelve pigs were euthanized seven days post-injection (n = 6/intervention). We performed autoradiography on hippocampus and prefrontal cortex (PFC) sections with [3H]UCB-J (SV2A), [3H]MDL100907 (5-HT2AR antagonist) and [3H]Cimbi-36 (5-HT2AR agonist). One day post psilocybin injection, we observed 4.42% higher hippocampal SV2A density and lowered hippocampal and PFC 5-HT2AR density (−15.21% to −50.19%). These differences were statistically significant in the hippocampus for all radioligands and in the PFC for [3H]Cimbi-36 only. Seven days post-intervention, there was still significantly higher SV2A density in the hippocampus (+9.24%) and the PFC (+6.10%), whereas there were no longer any differences in 5-HT2AR density. Our findings suggest that psilocybin causes increased persistent synaptogenesis and an acute decrease in 5-HT2AR density, which may play a role in psilocybin’s antidepressive effects.

Regional cerebral blood flow (rCBF) quantification using 123I-N-isopropyl-p-iodoamphetamine (123I-IMP) requires an invasive, one-time-only arterial blood sampling for measuring the 123I-IMP arterial blood radioactivity concentration (Ca10). The purpose of this study was to estimate Ca10 by machine learning (ML) using artificial neural network (ANN) regression analysis and consequently calculating rCBF and cerebral vascular reactivity (CVR) in the dual-table autoradiography (DTARG) method. This retrospective study included 294 patients who underwent rCBF measurements through the 123I-IMP DTARG. In the ML, the objective variable was defined by the measured Ca10, whereas the explanatory variables included 28 numeric parameters, such as patient characteristic values, total injection 123I-IMP radiation dose, cross-calibration factor, and the distribution of 123I-IMP count in the first scan. ML was performed with training (n = 235) and testing (n = 59) sets. Ca10 was estimated in testing set by our proposing model. Alternatively, the estimated Ca10 was also calculated via the conventional method. Subsequently, rCBF and CVR were calculated using estimated Ca10. Pearson's correlation coefficient (r-value) for the goodness of fit and the Bland-Altman analysis for assessing the potential agreement and bias were performed between the measured and estimated values. The r-value of Ca10 estimated by our proposed model was higher compared with the conventional method (0.81 and 0.66, respectively). In the Bland-Altman analysis, mean differences of 4.7 (95% limits of agreement (LoA): -18-27) and 4.1 (95% LoA: -35-43) were observed using proposed model and the conventional method, respectively. The r-values of rCBF at rest, rCBF after the acetazolamide challenge, and CVR calculated using the Ca10 estimated by our proposed model were 0.83, 0.80 and 0.95, respectively. Our proposed ANN-based model could accurately estimate the Ca10, rCBF, and CVR in DTARG. These results would enable non-invasive rCBF quantification in DTARG.

Regional cerebral blood flow (rCBF) quantification using 123I-N-isopropyl-p-iodoamphetamine (123I-IMP) requires an invasive, one-time-only arterial blood sampling for measuring the 123I-IMP arterial blood radioactivity concentration (Ca10). The purpose of this study was to estimate Ca10 by machine learning (ML) using artificial neural network (ANN) regression analysis and consequently calculating rCBF and cerebral vascular reactivity (CVR) in the dual-table autoradiography (DTARG) method. This retrospective study included 294 patients who underwent rCBF measurements through the 123I-IMP DTARG. In the ML, the objective variable was defined by the measured Ca10, whereas the explanatory variables included 28 numeric parameters, such as patient characteristic values, total injection 123I-IMP radiation dose, cross-calibration factor, and the distribution of 123I-IMP count in the first scan. ML was performed with training (n = 235) and testing (n = 59) sets. Ca10 was estimated in testing set by our proposing model. Alternatively, the estimated Ca10 was also calculated via the conventional method. Subsequently, rCBF and CVR were calculated using estimated Ca10. Pearson's correlation coefficient (r-value) for the goodness of fit and the Bland-Altman analysis for assessing the potential agreement and bias were performed between the measured and estimated values. The r-value of Ca10 estimated by our proposed model was higher compared with the conventional method (0.81 and 0.66, respectively). In the Bland-Altman analysis, mean differences of 4.7 (95% limits of agreement (LoA): -18-27) and 4.1 (95% LoA: -35-43) were observed using proposed model and the conventional method, respectively. The r-values of rCBF at rest, rCBF after the acetazolamide challenge, and CVR calculated using the Ca10 estimated by our proposed model were 0.83, 0.80 and 0.95, respectively. Our proposed ANN-based model could accurately estimate the Ca10, rCBF, and CVR in DTARG. These results would enable non-invasive rCBF quantification in DTARG.

Neurotransmitter receptors support the propagation of signals in the human brain. How receptor systems are situated within macro-scale neuroanatomy and how they shape emergent function remain poorly understood, and there exists no comprehensive atlas of receptors. Here we collate positron emission tomography data from more than 1,200 healthy individuals to construct a whole-brain three-dimensional normative atlas of 19 receptors and transporters across nine different neurotransmitter systems. We found that receptor profiles align with structural connectivity and mediate function, including neurophysiological oscillatory dynamics and resting-state hemodynamic functional connectivity. Using the Neurosynth cognitive atlas, we uncovered a topographic gradient of overlapping receptor distributions that separates extrinsic and intrinsic psychological processes. Finally, we found both expected and novel associations between receptor distributions and cortical abnormality patterns across 13 disorders. We replicated all findings in an independently collected autoradiography dataset. This work demonstrates how chemoarchitecture shapes brain structure and function, providing a new direction for studying multi-scale brain organization.Hansen et al. compile and share an atlas of neurotransmitter receptor/transporter densities in the human cortex and show that receptor achitecture reflects brain structure, function, dynamics, cognitive specialization and disease vulnerability.

Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the human brain and plays a key role in several brain functions and neuropsychiatric disorders such as anxiety, epilepsy, and depression. For decades, several in vivo and ex vivo techniques have been used to highlight the mechanisms of the GABA system, however, no studies have currently combined the techniques to create a high-resolution multimodal view of the GABA system. Here, we present a quantitative high-resolution in vivo atlas of the human brain benzodiazepine receptor sites (BZR) located on postsynaptic ionotropic GABAA receptors (GABAARs), generated on the basis of in vivo [11C]flumazenil Positron Emission Tomography (PET) data. Next, based on ex vivo autoradiography data, we transform the PET-generated atlas from binding values into BZR protein density. Finally, we examine the brain regional association between BZR protein density and ex vivo mRNA expression for the 19 subunits in the GABAAR, including an estimation of the minimally required expression of mRNA levels for each subunit to translate into BZR protein. This represents the first publicly available quantitative high-resolution in vivo atlas of the spatial distribution of BZR densities in the healthy human brain. The atlas provides a unique neuroscientific tool as well as novel insights into the association between mRNA expression for individual subunits in the GABAAR and the BZR density at each location in the brain.

Radiopharmaceutical therapy using α -emitting 225 Ac is an emerging treatment for patients with advanced metastatic cancers. Measurement of the spatial dose distribution in organs and tumors is needed to inform treatment dose prescription and reduce off-target toxicity, at not only organ but also sub-organ scales. Digital autoradiography with α -sensitive detection devices can measure radioactivity distributions at 20–40 μ m resolution, but anatomical characterization is typically limited to 2D. We collected digital autoradiographs across whole tissues to generate 3D dose volumes and used them to evaluate the simultaneous tumor control and regional kidney dosimetry of a novel therapeutic radiopharmaceutical for prostate cancer, [ 225 Ac]Ac-Macropa-PEG 4 -YS5, in mice. 22Rv1 xenograft-bearing mice treated with 18.5 kBq of [ 225 Ac]Ac-Macropa-PEG 4 -YS5 were sacrificed at 24 h and 168 h post-injection for quantitative α -particle digital autoradiography and hematoxylin and eosin staining. Gamma-ray spectroscopy of biodistribution data was used to determine temporal dynamics and 213 Bi redistribution. Tumor control probability and sub-kidney dosimetry were assessed. Heterogeneous 225 Ac spatial distribution was observed in both tumors and kidneys. Tumor control was maintained despite heterogeneity if cold spots coincided with necrotic regions. 225 Ac dose-rate was highest in the cortex and renal vasculature. Extrapolation of tumor control suggested that kidney absorbed dose could be reduced by 41% while maintaining 90% TCP. The 3D dosimetry methods described allow for whole tumor and organ dose measurements following 225 Ac radiopharmaceutical therapy, which correlate to tumor control and toxicity outcomes.

In tissue distribution studies of radiopharmaceuticals, quantitative whole-body autoradiography (QWBA) and oxidative combustion (OC) analysis are the two important methods that have not been compared using the same drug. Sprague-Dawley (SD) and Long-Evans (LE) rats, both of which are commonly used rodents in tissue distribution studies, have also not been compared using the same drug. Comparative studies are important for aiding the selection of appropriate experimental methods and animals. To evaluate the tissue distribution of [14C]Mefuparib (CVL218) in rats and assess its clinical safety, QWBA and OC analysis were used. The differences between the two methods were noted. Comparisons between the tissue distribution results of LE and SD rats were also done. The QWBA and OC distribution analysis showed that [14C]CVL218-related radioactivity could be distributed in 19 tissues. For 89.47% of the tissues, no significant differences were noted between the two methods. There were also no differences in the pharmacokinetics data for plasma and brain homogenates between LE and SD rats. However, the pharmacokinetics data for liver and kidney homogenates were seven-fold higher in LE rats than in SD ones. Both the OC and QWBA methods revealed that [14C]CVL218 could be widely distributed in the tissues of rats. The OC had a lower limit of quantification while QWBA provided a more comprehensive analysis of [14C]CVL218 distribution. More safety was associated with using LE rat data to estimate the dosimetry of [14C]CVL218 for the whole-body, for human radiolabeled mass balance studies.