The strength of Nuclear Medicine imaging are the compounds to be used as radioactive probes. Unfortunately there are many constraints both in relation to physiological parameters such as metabolism as well to compound related properties like lipophilicity or chemical stability. Due these constraints, many, otherwise promising, compounds could not be used in Nuclear Medicine imaging. Within this review a brief summary is given regarding possible limitations for imaging probes and approaches or techniques to overcome the constraints. Even so the review focuses on imaging with central active compounds, many of these problems appear likewise when targeting peripheral organs. Besides the established approaches to overcome limitations some new, so far not explored, directions are discussed. Finally, a potential new tool in imaging will be presented, a trojan horse approach for transportation of radioligands. Here, like in conventional drug development, lipid nanoparticles may have potential to be used as carrier systems in Nuclear Medicine as well. This, so far not explored, concept is briefly presented.

Vagus nerve stimulation (VNS) is the subject of exploration as an adjunct treatment for neurological disorders such as epilepsy, chronic migraine, pain, and depression. A non-invasive form of VNS is transcutaneous auricular VNS (taVNS). Combining animal models and positron emission tomography (PET) may lead to a better understanding of the elusive mechanisms of taVNS. We evaluated the acute effect of electrical stimulation of the left vagus nerve via the ear on brain synaptic vesicle glycoprotein 2A (SV2A) as a measure of presynaptic density and glucose metabolism in na & iuml;ve rats. Female Sprague-Dawley rats were imaged with [C-11]UCB-J (n = 11) or [F-18]fluorodeoxyglucose ([F-18]FDG) PET (n = 13) on two separate days, (1) at baseline, and (2) after acute unilateral left taVNS or sham stimulation (30 min). We calculated the regional volume of distribution (V-T) for [C-11]UCB-J and standard uptake values (SUV) for [F-18]FDG. We observed regional reductions of [C-11]UCB-J binding in response to taVNS ranging from 36% to 59%. The changes in taVNS compared to baseline were significantly larger than those induced by sham stimulation. The differences were observed bilaterally in the frontal cortex, striatum, and midbrain. The [F-18]FDG PET uptake remained unchanged following acute taVNS or sham stimulation compared to baseline values. This proof-of-concept study shows for the first time that acute taVNS for 30 min can modulate in vivo synaptic SV2A density in cortical and subcortical regions of healthy rats. Preclinical disease models and PET ligands of different targets can be a powerful combination to assess the therapeutic potential of taVNS.

Abstract Background Correct classification of estrogen receptor (ER) status is essential for prognosis and treatment planning in patients with breast cancer (BC). Therefore, it is recommended to sample tumor tissue from an accessible metastasis. However, ER expression can show intra- and intertumoral heterogeneity. 16α-[18F]fluoroestradiol ([18F]FES) Positron Emission Tomography/Computed Tomography (PET/CT) allows noninvasive whole-body (WB) identification of ER distribution and is usually performed as a single static image 60 min after radiotracer injection. Using dynamic whole-body (D-WB) PET imaging, we examine [18F]FES kinetics and explore whether Patlak parametric images ( $${K}_{i}$$ K i ) are quantitative and improve lesion visibility. Results This prospective study included eight patients with metastatic ER-positive BC scanned using a D-WB PET acquisition protocol. The kinetics of [18F]FES were best characterized by the irreversible two-tissue compartment model in tumor lesions and in the majority of organ tissues. $${K}_{i}$$ K i values from Patlak parametric images correlated with $${K}_{i}$$ K i values from the full kinetic analysis, r2 = 0.77, and with the semiquantitative mean standardized uptake value (SUVmean), r2 = 0.91. Furthermore, parametric $${K}_{i}$$ K i images had the highest target-to-background ratio (TBR) in 162/164 metastatic lesions and the highest contrast-to-noise ratio (CNR) in 99/164 lesions compared to conventional SUV images. TBR was 2.45 (95% confidence interval (CI): 2.25–2.68) and CNR 1.17 (95% CI: 1.08–1.26) times higher in $${K}_{i}$$ K i images compared to SUV images. These quantitative differences were seen as reduced background activity in the $${K}_{i}$$ K i images. Conclusion [18F]FES uptake is best described by an irreversible two-tissue compartment model. D-WB [18F]FES PET/CT scans can be used for direct reconstruction of parametric $${K}_{i}$$ K i images, with superior lesion visibility and $${K}_{i}$$ K i values comparable to $${K}_{i}$$ K i values found from full kinetic analyses. This may aid correct ER classification and treatment decisions. Trial registration ClinicalTrials.gov: NCT04150731, https://clinicaltrials.gov/study/NCT04150731

Estrogen receptors (ERs) play a multitude of roles in brain function and are implicated in various brain disorders. The use of positron emission tomography (PET) tracers for the visualization of ERs' intricate landscape has shown promise in oncology but remains limited in the context of brain disorders. Despite recent progress in the identification and development of more selective ligands for various ERs subtypes, further optimization is necessary to enable the reliable and efficient imaging of these receptors. In this perspective, we briefly touch upon the significance of estrogen signaling in the brain and raise the setbacks associated with the development of PET tracers for identification of specific ERs subtypes in the brain. We then propose avenues for developing efficient PET tracers to non-invasively study the dynamics of ERs in the brain, as well as neuropsychiatric diseases associated with their malfunction in a longitudinal manner. This perspective puts several potential candidates on the table and highlights the unmet needs and areas requiring further research to unlock the full potential of PET tracers for ERs imaging, ultimately aiding in deepening our understanding of ERs and forging new avenues for potential therapeutic strategies.

Carboxypeptidase II (CBPII) in brain metabolizes the neuroactive substance N‐acetyl‐L‐aspartyl‐L‐glutamate (NAGG) to yield the elements of glutamate and N‐acetyl‐aspartate (NAA). In peripheral organs, CBPII is known as prostrate specific membrane antigen (PSMA), which presents an important target for nuclear medicine imaging in prostate cancer. Available PSMA ligands for PET imaging do not cross the blood–brain barrier, and there is scant knowledge of the neurobiology of CBPII, despite its implication in the regulation of glutamatergic neurotransmission. In this study we used the clinical PET tracer [18F]‐PSMA‐1007 ([18F]PSMA) for an autoradiographic characterization of CGPII in rat brain. Ligand binding and displacement curves indicated a single site in brain, with KD of about 0.5 nM, and Bmax ranging from 9 nM in cortex to 19 nM in white matter (corpus callosum and fimbria) and 24 nM in hypothalamus. The binding properties of [18F]PSMA in vitro should enable its use for autoradiographic investigations of CBPII expression in animal models of human neuropsychiatric conditions.

Background & Aims: In Wilson disease (WD), copper accumulation and increased non-ceruloplasmin-bound copper in plasma lead to liver and brain pathology. To better understand the fate of non-ceruloplasmin-bound copper, we used PET/CT to examine the whole-body distribution of intravenously injected 64-copper (64Cu). Methods: Eight patients with WD, five heterozygotes, and nine healthy controls were examined by dynamic PET/CT for 90 min and static PET/CT up to 20 h after injection. We measured 64Cu activity in blood and tissue and quantified the kinetics by compartmental analysis.Results: Initially, a large fraction of injected 64Cu was distributed to extrahepatic tissues, especially skeletal muscle. Thus, across groups, extrahepatic tissues accounted for 45-58% of the injected dose (%ID) after 10 min, and 45-55% after 1 h. Kinetic analysis showed rapid exchange of 64Cu between blood and muscle as well as adipose tissue, with 64Cu retention in a secondary compartment, possibly mitochondria. This way, muscle and adipose tissue may protect the brain from spikes in nonceruloplasmin-bound copper. Tiny amounts of cerebral 64Cu were detected (0.2%ID after 90 min and 0.3%ID after 6 h), suggesting tight control of cerebral copper in accordance with a cerebral clearance that is 2-3-fold lower than in muscle. Compared to controls, patients with WD accumulated more hepatic copper 6-20 h after injection, and also renal copper at 6 h.Conclusion: Non-ceruloplasmin-bound copper is initially distributed into a number of tissues before being redistributed slowly to the eliminating organ, the liver. Cerebral uptake of copper is extremely slow and likely highly regulated. Our findings provide new insights into the mechanisms of copper control.Impact and implications: Maintaining non-ceruloplasmin-bound copper within the normal range is an important treatment goal in WD as this "free" copper is considered toxic to the liver and brain. We found that intravenously injected nonceruloplasmin-bound copper quickly distributed to a number of tissues, especially skeletal muscle, subcutaneous fat, and the liver, while uptake into the brain was slow. This study offers new insights into the mechanisms of copper control, which may encourage further research into potential new treatment targets. Clinical trial number: 2016-001975-59.(c) 2023 The Authors. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Wilson’s disease (WD) is a genetic disease with systemic accumulation of copper that leads to symptoms from the liver and brain. However, the underlying defects in copper transport kinetics are only partly understood. We sought to quantify hepatic copper turnover in patients with WD compared with heterozygote and control subjects using PET with copper‐64 (64Cu) as a tracer. Furthermore, we assessed the diagnostic potential of the method.

Introduction: The peripheral autonomic nervous system may be involved years before onset of motor symptoms in some patients with Parkinson's disease (PD). Specific imaging techniques to quantify the cholinergic nervous system in peripheral organs are an unmet need. We tested the hypothesis that patients with PD display decreased [18F]FEOBV uptake in peripheral organs - a sign of parasympathetic denervation. Methods: We included 15 PD patients and 15 age-and sex matched healthy controls for a 70 min whole-body dynamic positron emission tomography (PET) acquisition. Compartmental modelling was used for tracer ki-netic analyses of adrenal gland, pancreas, myocardium, spleen, renal cortex, muscle and colon. Standard uptake values (SUV) at 60-70 min post injection were also extracted for these organs. Additionally, SUVs were also determined in the total colon, prostate, parotid and submandibular glands. Results: We found no statistically significant difference of [18F]FEOBV binding parameters in any organs between patients with PD and healthy controls, although trends were observed. The pancreas SUV showed a 14% reduction in patients (P = 0.021, not statistically significant after multiple comparison correction). We observed a trend towards lower SUVs in the pancreas, colon, adrenal gland, and myocardium of PD patients with versus without probable REM sleep behavior disorder. Conclusion: [18F]FEOBV PET may not be a sensitive marker for parasympathetic degeneration in patients with PD.

Abstract Background The autonomic nervous system is frequently affected in some neurodegenerative diseases, including Parkinson’s disease and Dementia with Lewy bodies. In vivo imaging methods to visualize and quantify the peripheral cholinergic nervous system are lacking. By using [18F]FEOBV PET, we here describe the peripheral distribution of the specific cholinergic marker, vesicular acetylcholine transporters (VAChT), in human subjects. We included 15 healthy subjects aged 53–86 years for 70 min dynamic PET protocol of peripheral organs. We performed kinetic modelling of the adrenal gland, pancreas, myocardium, renal cortex, spleen, colon, and muscle using an image-derived input function from the aorta. A metabolite correction model was generated from venous blood samples. Three non-linear compartment models were tested. Additional time-activity curves from 6 to 70 min post injection were generated for prostate, thyroid, submandibular-, parotid-, and lacrimal glands. Results A one-tissue compartment model generated the most robust fits to the data. Total volume-of-distribution rank order was: adrenal gland > pancreas > myocardium > spleen > renal cortex > muscle > colon. We found significant linear correlations between total volumes-of-distribution and standard uptake values in most organs. Conclusion High [18F]FEOBV PET signal was found in structures with known cholinergic activity. We conclude that [18F]FEOBV PET is a valid tool for estimating VAChT density in human peripheral organs. Simple static images may replace kinetic modeling in some organs and significantly shorten scan duration. Clinical Trial Registration Trial registration: NCT, NCT03554551. Registered 31 May 2018. https://clinicaltrials.gov/ct2/show/NCT03554551?term=NCT03554551&draw=2&rank=1 .

After introduction of the first commercial combined PET and/or CT technology in 2001, this diagnostic tool quickly became a clinical success and was considered the fastest growing diagnostic imaging technology ever. However, this technique is very dependent on the availability of positron emitting isotopes and radiochemistry to incorporate the radioactive isotopes into larger molecules of physiological interest. Within this review article a historical overview starting with the first applications of positron emitting isotopes in the 1930's is presented. Afterwards a more detailed presentation summarizing the physical basis and advancements in cyclotron technology is given. Radiochemical and/or pharmaceutical advancements are presented systematically for the most significant isotopes like 15O, 13N, 11C, 18F and 68Ga Besides these major PET isotopes, advancements of other radio-metals and future perspectives regarding application of new radionuclides will be discussed. Finally, very interesting new and compact accelerator technology and microfluidic chemical reaction approaches will be discussed. Especially, new compact accelerator technology might be new quantum leap within this radiodiagnostic technology and might result in even further prevalence, ultimately envisioned by the dose-on-demand concept that will be briefly discussed.

We asked if sensation-seeking is linked to premorbid personality characteristics in patients with addictive disorders, or the characteristics follow the sensation-seeking activity. We interpreted the former as a state associated with normal rates of dopamine synthesis, and the latter as a trait of individuals with abnormally high rates of synthesis. We previously determined dopaminergic receptor density in striatum, and we now tested the hypothesis that an elevated dopaminergic condition with increased extracellular dopamine and receptor density follows increased dopamine synthesis capacity in highly sensation-seeking individuals, as measured by positron emission tomography of 18 men with tracer fluorodopa (FDOPA). We detected a site in left caudate nucleus where the volume of distribution of FDOPA-derived metabolites correlated negatively with FDOPA metabolite turnover, consistent with decreased metabolite breakdown in highly sensation-seeking subjects. High rates of sensation-seeking attenuated the dopamine turnover in association with a low rate of dopamine recycling, low dopamine oxidation, and elevated extracellular dopamine and receptors in caudate nucleus. In contrast, low rates of sensation-seeking were associated with rapid dopamine recycling, rapid dopamine oxidation, low extracellular dopamine, and low receptor density. We conclude that the modulation of dopaminergic neurotransmission associated with sensation-seeking is a state of sensation-seeking, rather than a trait of personality following abnormal regulation of dopaminergic neurotransmission.

BACKGROUND:The radiofluorinated levodopa analogue 6-[18F]F-L-DOPA (3,4-dihydroxy-6-18F-L-phenylalanine) is a commonly employed radiotracer for PET/CT imaging of multiple oncological and neurological indications. An unusually large number of different radiosyntheses have been published to the point where two different Ph. Eur. monographs exist depending on whether the chemistry relies on electrophilic or nucleophilic radiosubstitution of appropriate chemical precursors. For new PET imaging sites wishing to adopt [18F]FDOPA into clinical practice, selecting the appropriate production process may be difficult and dependent on the clinical needs of the site.METHODS:Data from four years of [18F]FDOPA production at three different clinical sites are collected and compared. These three sites, Aarhus University Hospital (AUH), Odense University Hospital (OUH), and Herlev University Hospital (HUH), produce the radiotracer by different radiosynthetic routes with AUH adopting an electrophilic strategy, while OUH and HUH employ two different nucleophilic approaches. Production failure rates, radiochemical yields, and molar activities are compared across sites and time. Additionally, the clinical use of the radiotracer over the time period considered at the different sites are presented and discussed.RESULTS:The electrophilic substitution route suffers from being demanding in terms of cyclotron operation and maintenance. This challenge, however, was found to be compensated by a production failure rate significantly below that of both nucleophilic approaches; a result of simpler chemistry. The five-step nucleophilic approach employed at HUH produces superior radiochemical yields compared to the three-step approach adopted at OUH but suffers from the need for more comprehensive synthesis equipment given the multi-step nature of the procedure, including HPLC purification. While the procedure at OUH furnishes the lowest radiochemical yield of the synthetic routes considered, it produces the highest molar activity. This is of importance across the clinical applications of the tracer discussed here, including dopamine synthesis in striatum of subjects with schizophrenia and congenital hyperinsulinism in infants.CONCLUSION:For most sites either of the two nucleophilic substitution strategies should be favored. However, which of the two will depend on whether a given site wishes to optimize the radiochemical yield or the ease of the use.

Objective Imaging activated glutamate N-methyl-D-aspartate receptor ion channels (NMDAR-ICs) using positron emission tomography (PET) has proved challenging due to low brain uptake, poor affinity and selectivity, and high metabolism and dissociation rates of candidate radioligands. The radioligand [F-18]GE-179 is a known use-dependent marker of NMDAR-ICs. We studied whether interictal [F-18]GE-179 PET would detect foci of abnormal NMDAR-IC activation in patients with refractory focal epilepsy. Methods Ten patients with refractory focal epilepsy and 18 healthy controls had structural magnetic resonance imaging (MRI) followed by a 90-min dynamic [F-18]GE-179 PET scan with simultaneous electroencephalography (EEG). PET and EEG findings were compared with MRI and previous EEGs. Standard uptake value (SUV) images of [F-18]GE-179 were generated and global gray matter uptake was measured for each individual. To localize focal increases in uptake of [F-18]GE-179, the individual SUV images were interrogated with statistical parametric mapping in comparison to a normal database. Additionally, individual healthy control SUV images were compared with the rest of the control database to determine their prevalence of increased focal [F-18]GE-179 uptake. Results Interictal [F-18]GE-179 PET detected clusters of significantly increased binding in eight of 10 patients with focal epilepsy but none of the controls. The number of clusters of raised [F-18]GE-179 uptake in the patients with epilepsy exceeded the focal abnormalities revealed by the simultaneously recorded EEG. Patients with extensive clusters of raised [F-18]GE-179 uptake showed the most abnormal EEGs. Significance Detection of multiple foci of abnormal NMDAR-IC activation in 80% of our patients with refractory focal epilepsy using interictal [F-18]GE-179 PET could reflect enhanced neuronal excitability due to chronic seizure activity. This indicates that chronic epileptic activity is associated with abnormal NMDAR ion channel activation beyond the initial irritative zones. [F-18]GE-179 PET could be a candidate marker for identifying pathological brain areas in patients with treatment-resistant focal epilepsy.

C Radiolabeling of anle253b: a Putative PET Tracer for Parkinson’s Disease That Binds to α-Synuclein Fibrils in vitro and Crosses the Blood-Brain Barrier Andreas Maurer,* Andrei Leonov, Sergey Ryazanov, Kristina Herfert, Laura Kuebler, Sabrina Buss, Felix Schmidt, Daniel Weckbecker, Ruth Linder, Dirk Bender, Armin Giese, Bernd J. Pichler, and Christian Griesinger*© 2020 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

There is an urgent clinical need for imaging of α‐synuclein (αSyn) fibrils, the hallmark biomarker for Parkinson's disease, in neurodegenerative disorders. Despite immense efforts, promising tracer candidates for nuclear imaging of αSyn are rare. Diphenyl pyrazoles are known modulators of αSyn aggregation and thus bear potential for non‐invasive detection of this biomarker in vivo. Here we demonstrate high‐affinity binding of the family member anle253b to fibrillar αSyn and present a high‐yielding site‐selective radiosynthesis route for 11C radiolabeling using in‐situ generated [11C]formaldehyde and reductive methylation. Radio‐HPLC of the tracer after incubation with rat serum in vitro shows excellent stability of the molecule. Positron emission tomography in healthy animals is used to assess the pharmacokinetics and biodistribution of the tracer, showing good penetration of the blood–brain barrier and low background binding to the non‐pathological brain.

The development of bacteria-specific infection radiotracers is of considerable interest to improve diagnostic accuracy and enabling therapy monitoring. The aim of this study was to determine if the previously reported radiolabelled 1,4,7,10-tetraazacyclododecane-N,N',N″,N‴-tetraacetic acid (DOTA) conjugated peptide [68 Ga]Ga-DOTA-K-A9 could detect a staphylococcal infection in vivo and distinguish it from aseptic inflammation. An optimized [68 Ga]Ga-DOTA-K-A9 synthesis omitting the use of acetone was developed, yielding 93 ± 0.9% radiochemical purity. The in vivo infection binding specificity of [68 Ga]Ga-DOTA-K-A9 was evaluated by micro positron emission tomography/magnetic resonance imaging of 15 mice with either subcutaneous Staphylococcus aureus infection or turpentine-induced inflammation and compared with 2-deoxy-2-[18 F]fluoro-D-glucose ([18 F]FDG). The scans showed that [68 Ga]Ga-DOTA-K-A9 accumulated in all the infected mice at injected doses ≥3.6 MBq. However, the tracer was not found to be selective towards infection, since the [68 Ga]Ga-DOTA-K-A9 also accumulated in mice with inflammation. In a concurrent in vitro binding evaluation performed with a 5-carboxytetramethylrhodamine (TAMRA) fluorescence analogue of the peptide, TAMRA-K-A9, the microscopy results suggested that TAMRA-K-A9 bound to an intracellular epitope and therefore preferentially targeted dead bacteria. Thus, the [68 Ga]Ga-DOTA-K-A9 uptake observed in vivo is presumably a combination of local hyperemia, vascular leakiness and/or binding to an epitope present in dead bacteria.