Positron emission tomography is an imaging technique with applications in clinical settings as well as in basic research for the study of biological processes. A PET tracer, a biologically active molecule where a positron-emitting radioisotope such as carbon-11 has been incorporated, is used for the studies. Development of robust methods for incorporation of the radioisotope is therefore of the utmost importance. The urea functional group is present in many biologically active compounds and is thus an attractive target for incorporation of carbon-11 in the form of [C-11] carbon monoxide. Starting with amines and [C-11] carbon monoxide, both symmetrical and unsymmetrical C-11-labelled ureas were synthesised via a palladium(II)-mediated oxidative carbonylation and obtained in decay-corrected radiochemical yields up to 65%. The added advantage of using [C-11] carbon monoxide was shown by the molar activity obtained for an inhibitor of soluble epoxide hydrolase (247 GBq/mu mol-319 GBq/mu mol). DFT calculations were found to support a reaction mechanism proceeding through an C-11-labelled isocyanate intermediate.

The cholinergic system is involved in neurodegenerative diseases, and visualization of cholinergic innervations with positron emission tomography (PET) would be a useful tool in understanding these diseases. A ligand for the vesicular acetylcholine transporter (VAChT), acknowledged as a marker for cholinergic neurons, could serve as such a PET tracer. The aim was to find a VAChT PET tracer using a library concept to create a small but diverse library of labeled compounds. From the same precursor and commercially available aryl iodides 6a-f, six potential VAChT PET tracers, [C-11]-(+/-)5a-f, were C-11-labeled by a palladium (0)-mediated aminocarbonylation, utilizing a standard protocol. The labeled compounds [C-11]-(+/-)5a-f were obtained in radiochemical purities >95% with decay-corrected radiochemical yields and specific radioactivities between 4-25% and 124-597 GBq/mu mol, respectively. Autoradiography studies were then conducted to assess the compounds binding selectivity for VAChT. Labeled compounds [C-11]-(+/-)5d and [C-11]-(+/-)5e showed specific binding but not enough to permit further preclinical studies. To conclude, a general method for a facile synthesis and labeling of a small piperazine-based library of potential PET tracers for imaging of VAChT was shown, and in upcoming work, another scaffold will be explored using this approach.

A novel, mild and facile preparation of alkyl amides from unactivated alkyl iodides employing a fac-Ir(ppy)(3)-catalyzed radical aminocarbonylation protocol has been developed. Using a two-chambered system, alkyl iodides, fac-Ir(ppy)(3), amines, reductants, and CO gas (released ex situ from Mo(CO)(6)), were combined and subjected to an initial radical reductive dehalogenation generating alkyl radicals, and a subsequent aminocarbonylation with amines affording a wide range of alkyl amides in moderate to excellent yields.

Background: Of interest to women's mental health, a wealth of studies suggests sex differences in nicotine addiction and treatment response, but their psychoneuroendocrine underpinnings remain largely unknown. A pathway involving sex steroids could indeed be involved in the behavioural effects of nicotine, as it was found to inhibit aromatase in vitro and in vivo in rodents and non-human primates, respectively. Aromatase regulates the synthesis of oestrogens and, of relevance to addiction, is highly expressed in the limbic brain.

Methods: The present study sought to investigate in vivo aromatase availability in relation to exposure to nicotine in healthy women. Structural magnetic resonance imaging and two [11C]cetrozole positron emission tomography (PET) scans were performed to assess the availability of aromatase before and after administration of nicotine. Gonadal hormones and cotinine levels were measured. Given the region-specific expression of aromatase, a ROI -based approach was employed to assess changes in [11C]cetrozole non-displaceable binding potential.

Results: The highest availability of aromatase was found in the right and left thalamus. Upon nicotine exposure, [11C]cetrozole binding in the thalamus was acutely decreased bilaterally (Cohen's d =-0.99). In line, cotinine levels were negatively associated with aromatase availability in the thalamus, although as non-significant trend.

Conclusions: These findings indicate acute blocking of aromatase availability by nicotine in the thalamic area. This suggests a new putative mechanism mediating the effects of nicotine on human behaviour, particularly relevant to sex differences in nicotine addiction.

Herein, novel hepatitis C virus NS3/4A protease inhibitors based on a P2 pyrimidinyloxyphenylglycine in combination with various regioisomers of an aryl acyl sulfonamide functionality in P1 are presented. The P1′ 4-(trifluoromethyl)phenyl side chain was shown to be particularly beneficial in terms of inhibitory potency. Several inhibitors with K_i-values in the nanomolar range were developed and included identification of promising P3-truncated inhibitors spanning from P2–P1′. Of several different P2 capping groups that were evaluated, a preference for the sterically congested Boc group was revealed. The inhibitors were found to retain inhibitory potencies for A156T, D168V, and R155K variants of the protease. Furthermore, in vitro pharmacokinetic profiling showed several beneficial effects on metabolic stability as well as on apparent intestinal permeability from both P3 truncation and the use of the P1′ 4-(trifluoromethyl)phenyl side chain.

The Suzuki-type cross coupling reaction is a palladium-mediated multistepreaction that has been used to synthesize several11C-labeled tracers for PET.However, the impact of the selected organoborane reagent and reactionmedium on the radiochemical yield (RCY) has not been thoroughly investi-gated. To bridge this gap, we studied the synthesis of 1-[11C]methyl-naphthalene using four different organoborane precursors in reactionsperformed in DMF/water and THF/water. In the synthesis of 1-[11C]methyl-naphthalene, the best radiochemical yields (RCYs), approximately 50%,were obtained with boronic acid and pinacol ester precursors, whereasless than 4% RCY was obtained when performing the reaction with theN-methylimidodiacetic acid boronic ester (MIDA ester) precursor. 1-[11C]methylnaphthalene was obtained in higher yields in almost all syntheses per-formed in THF/water as compared to DMF/water. This observation was in linewith previously reported results for [11C]UCB-J, a tracer for the synaptic vesi-cle glycoprotein 2A (SV2A) receptor, that also was obtained in higher RCYwhen synthesized in THF/water. The same trend was observed with [11C]cetrozole, where the RCY was more than doubled in THF/water compared tothe previously published synthesis performed in DMF. These results suggestthat THF/water could be the preferred reaction medium when producing PETtracers via the Suzuki-type coupling reaction.

Herein, new ligands for the vesicular acetylcholine transporter (VAChT), based on a benzovesamicol scaffold, are presented. VAChT is acknowledged as a marker for cholinergic neurons and a positron emission tomography tracer for VAChT could serve as a tool for quantitative analysis of cholinergic neuronal density. With an easily accessible triflate precursor, aminocarbonylations were utilized to evaluate the chemical space around the C5 position on the tetrahydronaphthol ring. Synthesized ligands were evaluated for their affinity and selectivity for VAChT. Small, preferably aromatic, N-substituents proved to be more potent than larger substituents. Of the fifteen compounds synthesized, benzyl derivatives (+/-)-7i and (+/-)-7l had the highest affinities for VAChT. Compound (+/-)-7i was chosen to investigate the importance of stereochemistry for binding to VAChT and selectivity toward the sigma(1) and sigma(2) receptors. Enantiomeric resolution gave (+/-)-7i and (-)-7i, and the eutomer showed seven times better affinity. Although racemate (+/-)-7i was initially promising, the affinity of (-)-7i for VAChT was not better than 56.7 nM which precludes further preclinical evaluation. However, the nanomolar binding together with the ready synthesis of [C-11]-(+/-)-7i shows that (-)-7i can serve as a scaffold for future optimizations to provide improved C-11-labelled VAChT PET tracers.

Herein, a simple and efficient method for the palladium-catalyzed carbonylation of aryl boronic acids with unactivated alkyl iodides and bromides under visible-light irradiation, ambient temperature and low CO-pressure is presented. Notably, the procedure uses readily available equipment and an inexpensive palladium catalyst to generate the key alkyl radical intermediate. These mild conditions enabled the synthesis of a range of functionalized aryl alkyl ketones including the antipsychotic drug, melperone.

Over the past decade, visible-light photocatalysis has emerged as one of the brightest and most dynamic fields in modern organic chemistry. By employing a transition-metal- or organic-dye-based photocatalyst in conjunction with a low-energy visible-light source, this synthetic manifold allows the facile generation of radical intermediates that can subsequently be directed through a wide range of transformations. Although initial studies focused largely on the functionalization of stabilized radical intermediates, over the past few years significant efforts have been directed towards the functionalization of challenging unactivated radical precursors. In this review we summarize the recent developments in the use of visible-light photocatalysis for the functionalization of unactivated C(sp(3))-substrates.

Positron emission tomography (PET) is a highly valuable imaging technique with many clinical applications. The possibility to study physiological and biochemical processes in vivo also makes PET an important tool in drug discovery. Of importance is the possibility of labelling the compound of interest with a positron-emitting radionuclide, such as carbon-11. Carbonylation reactions with [11C]carbon monoxide ([11C]CO) has been used to label a number of molecules containing a carbonyl derivative, such as amides and esters, with carbon-11. Presented herein is the palladium-mediated carbonylative synthesis of [carbonyl-11C]acyl amidines and their subsequent cyclization to 11C labeled 1,2,4-oxadiazoles. Starting from amidines, [11C]CO, and either aryl iodides or aryl bromides, [carbonyl-11C]acyl amidines were synthesized and isolated in good to very good radiochemical yields (RCY). The 11C-labeled 1,2,4-oxadiazoles were synthesized without the isolation of the intermediate [carbonyl-11C]acyl amidines and isolated in useful RCYs, including the NF-E2-related factor 2 activator DDO-7263. 3-Phenyl-5-(4-tolyl)-1,2,4-(5-11C)oxadiazole was synthesized and isolated with a clinically relevant molar activity. The broadened substrate scope, together with the good RCY and high Am, demonstrates the utility of this method for the incorporation of carbon-11 into acyl amidines and 1,2,4-oxadiazoles, structural motifs of pharmacological interest.

A protocol for the carbonylative synthesis of acyl amidines from aryl halides, amidines, and carbon monoxide catalyzed by Pd(0) is reported herein. Notably, carbon monoxide is generated ex situ from a solid CO source, and several productive palladium ligands were identified with complementary benefits and substrate scope. Furthermore, sequential one-pot, two-step protocols for the synthesis of 1,2,4-triazoles and 1,2,4-oxadiazoles via acyl amidine intermediates are reported. In addition, this approach was extended to isotopic labeling using [¹¹C]carbon monoxide to allow, for the first time, synthesis of ¹¹C-labeled acyl amidines as well as a ¹¹C-labeled 1,2,4-oxadiazole.

Purpose

[¹¹C]Metomidate positron emission tomography (PET) is currently used for staging of adrenocortical carcinoma and for lateralization in primary aldosteronism (PA). Due to the short half-life of carbon-11 and a high non-specific liver uptake of [¹¹C]metomidate there is a need for improved adrenal imaging methods. In a previous pre-clinical study para-chloro-2-[¹⁸F]fluoroethyletomidate has been proven to be a specific adrenal tracer. The objective is to perform a first evaluation of para-chloro-2-[¹⁸F]fluoroethyletomidate positron emission computed tomography ([¹⁸F]CETO-PET/CT) in patients with adrenal tumours and healthy volunteers.

Methods

Fifteen patients underwent [¹⁸F]CETO-PET/CT. Five healthy volunteers were recruited for test-retest analysis and three out of the five underwent additional [¹⁵O]water PET/CT to measure adrenal blood flow. Arterial blood sampling and tracer metabolite analysis was performed. The kinetics of [¹⁸F]CETO were assessed and simplified quantitative methods were validated by comparison to outcome measures of tracer kinetic analysis.

Results

Uptake of [¹⁸F]CETO was low in the liver and high in adrenals. Initial metabolization was rapid, followed by a plateau. The kinetics of [¹⁸F]CETO in healthy adrenals and all adrenal pathologies, except for adrenocortical carcinoma, were best described by an irreversible single-tissue compartment model. Standardized uptake values (SUV) correlated well with the uptake rate constant K₁. Both K₁ and SUV were highly correlated to adrenal blood flow in healthy controls. Repeatability coefficients of K₁, SUV_65–70, and SUV₁₂₀ were 25, 22, and 17%.

Conclusions

High adrenal uptake combined with a low unspecific liver uptake suggests that ¹⁸F]CETO is a suitable tracer for adrenal imaging. Adrenal SUV, based on a whole-body scan at 1 h p.i., correlated well with the net uptake rate K_i.

Trial registration

ClinicalTrials.gov, NCT05361083 Retrospectively registered 29 April 2022. at, https://clinicaltrials.gov/ct2/show/NCT05361083

Iridium stands at the center of a vortex of electrons that are transferred to and from the surrounding reaction components in this radical aminocarbonylation method. The combination of visible-light irradiation and low-pressure ex situ carbon monoxide generation makes this an attractive and operationally simple approach for preparing β-hydride-containing alkyl amides. Additional cover art acknowledgements: Bobo Skillinghaug and Johan Sjöstedt. More information can be found in the Full Paper by L. R. Odell et al. on page 9155 ff.