11CO2 fixation: a renaissance in PET radiochemistry

Abstract

Carbon-11 labelled carbon dioxide is the cyclotron-generated feedstock reagent for most positron emission tomography (PET) tracers using this radionuclide. Most carbon-11 labels, however, are installed using derivative reagents generated from [(11)C]CO2. In recent years, [(11)C]CO2 has seen a revival in applications for the direct incorporation of carbon-11 into functional groups such as ureas, carbamates, oxazolidinones, carboxylic acids, esters, and amides. This review summarizes classical [(11)C]CO2 fixation strategies using organometallic reagents and then focuses on newly developed methods that employ strong organic bases to reversibly capture [(11)C]CO2 into solution, thereby enabling highly functionalized labelled compounds to be prepared. Labelled compounds and radiopharmaceuticals that have been translated to the clinic are highlighted.

Fig. 1

Cyclotron produced [¹¹C]CO₂has been recently applied to radiolabelling of structurally complex carboxylic acids and amides, carbamates, oxazolidinones, and ureas. *Trapping is typically done with molecular sieves or liquid nitrogen and release Is achieved by heating.

Scheme 1

¹¹CO₂-fixations using strongly basic organometallic reagents such as Grignard reagents (A); organolithium reagents (B and C); and silanamines (D). TMS: trimethylsilyl; asterisk denotes ¹¹C.

Scheme 2

Synthesis of [¹¹C]ureas by [¹¹C]CO₂-fixation. (A) Synthesis of parent [¹¹C]urea using LHMDS and aqueous ammonium chloride. (B) Synthesis of symmetrical and unsymmetrical substituted [¹¹C]ureas by activation of an ammonium carbamate intermediate with POCl₃. The utility of this reaction was greatly expanded by judicious control of reaction conditions to favour unsymmetrical products. TEA: triethylamine; TMS: trimethylsilyl; asterisk denotes ¹¹C.

Scheme 3

Synthesis of [¹¹C]phenylisocyanate and [¹¹C]ureas by fixation with N-phenyl(triphenylphosphin)imine. Asterisk denotes ¹¹C.

Scheme 4

[¹¹C-carbonyl]Carbamates can be synthesized by nucleophilic alkylation of the trapped [¹¹C]CO₂ followed by amine substitution (left), or through activation of an intermediate carbamate salt using POCl₃ (right). DBU: 1,8-Diazabicyclo[5.4.0]undec-7-ene; Q: fixation base; R: H, phenyl, vinyl, alkyl; X: Cl, Br, I, OTs, sulfate; asterisk denotes ¹¹C.

Scheme 5

(A) Radiosynthesis of [¹¹C]CURB; (B) Mechanism of FAAH radiolabelling with [¹¹C]CURB; the radiolabel must be placed on the carbonyl or N-alkyl fragment of the tracer to effectively measure levels of FAAH in the brain. Asterisk denotes ¹¹C.

Scheme 6

Cu(I) catalyzes¹¹C-carboxylation of boronic acid esters. The products can be elaborated to ¹¹C-esters and ¹¹C-amides. TMEDA: N,N,N′,N′-tetramethylethylenediamine; asterisk denotes ¹¹C.