A synthetic pathway for PET-labeled amides is described using rhodium-catalyzed coupling of organozinc iodide reagents and in situ prepared carbon-11 isocyanates. A scope prepared using carbon-12 isocyanates yielded products from 13-87% using readily prepared sp 3 and sp 2 organozinc iodides. By manipulation of fixation, dehydration, and coupling conditions, the incorporation of [ 11 C]CO2 into 11 C-amide products proceeded in moderate to strong yields, as determined by radioHPLC. Among the compounds prepared are the biologically-relevant tert-butyl protected [ 11 C]N-acetyl glutamic acid ([ 11 C]6d), the agrochemical [ 11 C]propanil ([ 11 C]6f), and a pharmaceutically-relevant [ 11 C]acetanilide ([ 11 C]4m). The synthetic utility of the labeling methodology was demonstrated through the isolation of [ 11 C]N-(4-fluorophenyl)-4-methoxybenzamide ([ 11 C]6g) with a molar activity of 267 GBq•mol -1 and a radioactivity yield of 12%, 21 minutes after beginning of synthesis.

Iminophosphoranes are coupled with CO2 and carbon-, nitrogen-, oxygen-, and sulfur-based nucleophiles to synthesize acyclic (radio)pharmaceuticals in high yield.

Matrix metalloproteinase-13 (MMP-13) plays a critical role in the progression of unstable atherosclerosis. A series of highly potent and selective MMP-13 inhibitors were synthesized around a quinazoline-2-carboxamide scaffold to facilitate radiolabeling with fluorine-18 or carbon-11 positron-emitting nuclides and visualization of atherosclerotic plaques. In vitro enzyme inhibition assays identified three compounds as promising radiotracer candidates. Efficient automated radiosyntheses provided [ 11 C]5b, [ 11 C]5f, and [ 18 F]5j and enabled pharmacokinetic characterization in atherosclerotic mice. The radiotracers displayed substantial differences in their distribution and excretion. Most favorably for vascular imaging, [ 18 F]5j exhibited low uptake in metabolic organs with minimal retention of myocardial radioactivity, substantial renal clearance, and high metabolic stability in plasma. Ex vivo aortic autoradiography and competition studies revealed that [ 18 F]5j specifically binds to MMP-13 within atherosclerotic plaques and localizes to lipid-rich regions. This study demonstrates the utility of the quinazoline-2-carboxamide scaffold for MMP-13 selective positron emission tomography (PET) radiotracer development and identifies [ 18 F]5j for imaging atherosclerosis.

Dysfunction of the cardiac sympathetic nervous system contributes to the development of cardiovascular diseases including ischemia, heart failure, and arrhythmias. Molecular imaging probes such as meta-[ 123 I]iodobenzylguanidine have demonstrated the utility of assessing neuronal integrity by targeting norepinephrine transporter (NET, uptake-1). However, current radiotracers can report only on innervation due to suboptimal kinetics and lack sensitivity to NET in rodents, precluding mechanistic studies in these species. The objective of this work was to characterize myocardial sympathetic neuronal uptake mechanisms and kinetics of the positron emission tomography (PET) radiotracer meta-[ 18 F]fluorobenzylguanidine ([ 18 F]mFBG) in rats. Automated synthesis using spirocyclic iodonium(III) ylide radiofluorination produces [ 18 F]mFBG in 24 ± 1% isolated radiochemical yield and 30−95 GBq/μmol molar activity. PET imaging in healthy rats delineated the left ventricle, with monoexponential washout kinetics (k mono = 0.027 ± 0.0026 min −1 , A mono = 3.08 ± 0.33 SUV). Ex vivo biodistribution studies revealed tracer retention in the myocardium, while pharmacological treatment with selective NET inhibitor desipramine, nonselective neuronal and extraneuronal uptake-2 inhibitor phenoxybenzamine, and neuronal ablation with neurotoxin 6hydroxydopamine reduced myocardial retention by 33, 76, and 36%, respectively. Clearance of [ 18 F]mFBG from the myocardium was unaffected by treatment with uptake-1 and uptake-2 inhibitors following peak myocardial activity. These results suggest that myocardial distribution of [ 18 F]mFBG in rats is dependent on both NET and extraneuronal transporters and that limited reuptake to the myocardium occurs. [ 18 F]mFBG may therefore prove useful for imaging intraneuronal dysfunction in small animals.

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