Organotechnetium chemistry is the science of describing the physical properties, synthesis, and reactions oforganotechnetium compounds, which areorganometallic compounds containingcarbon-to-technetiumchemical bonds. The most common organotechnetium compounds arecoordination complexes used asradiopharmaceutical imaging agents.^[1][2]

In general, organotechnetium compounds are not typically used inchemical reactions orcatalysis due to theirradioactivity. Research on technetium chemistry is often done in conjunction withrhenium as aisoelectronic non-radioactive alternative to technetium.^[3]

Technetium were first used as a radiopharmaceutical in 1961.^[4] Of the radiopharmaceuticals in clinical use forSPECT (single photon emission computed tomography), a majority of the compounds are^99mTc complexes.^[5] Three generations of technetium radiopharmaceuticals currently exist and are used. The first generation do not localize specifically and are considered perfusion agents. Second generation has apeptide based targeting portion. The third generation of technetium radiopharmaceuticals features organotechnetium compounds that can localize in the body in abiomimetic manner.^[6][7][8]

A vast majority of technetium compounds used in radiopharmaceutical imaging and diagnosis areinorganic coordination complexes. There are a number of “classical” organometallic organotechnetium compounds, specifically containing carbon-technetium bonds are in clinical use. These organotechnetium compounds are mostly seen as technetium tri-carbonyl compounds and technetiumcyclopentadienyl compounds.

One of the most prominent radio pharmaceutical compounds in clinical use is Cardiolie^®, also known as^99mTc-Sestamibi. This organotechnetium compound is applied formyocardial imaging. The d⁶electron configuration is highly stable due to its lowoxidation state.^[9] The Tc(I) complex is further stabilized by the high reducing potential of theisonitrile ligands.^[10]

The abovepiano-stool organotechnetium complex is a third generation radiopharmaceutical. The cyclopentadienyl ligand acts as a bio isostere to a phenyl group in theamino acidphenylalanine.^[11]

Radioactive^99mTc is obtained in thepertechnetate form in dilute aqueous solution from⁹⁹Mo/^99mTc generators. Pertechnetate can then be made into more usefulcarbonyl and hydrate precursors for subsequent synthesis into technetate complexes.

As the starting radiometals are most available in aqueous solution due to method of isolation, the chemistry for synthesis of technetate compounds must be done in aqueous solution.

The study of technetium compounds is typically done in conjugation with rhenium as an isoelectronic and non-radioactive alternative to technetium.

For^99mTc and¹⁸⁸Re, the synthesis of compounds start with pertechnetate orperrhenate insaline at low concentration, obtained from⁹⁹Mo/^99mTc and¹⁸⁸W/¹⁸⁸Re generators. The aquo tricarbonyl precursors are useful for accessing Tc and Re complexes. The metals have d⁶ low-spin electronic configuration, providing highkinetic stability, and highly stable M-C bonds. Consequently, the three CO ligands always remain coordinated, while ligands readily replace the three water molecules. Typical organotechnetium compounds thus feature the tricarbonyl motif.

Typical methods of organometallic compounds synthesis difficult to utilize. To be useful as a radiopharmaceutical, the reaction should be done in an aqueous saline solution that can be injected into the body intravenously.

A double ligand transfer (DLT) reaction was developed by Martin Wenzel for synthesis of organotechnetium/organorhenium complexes.^[12] The reaction features the synthesis of organotechnetium piano-stool compounds fromferrocene. The reaction was further studied and optimized byKatzenellegbogen.^[13] Unfortunately, the utility of this method in the synthesis of radiopharmaceuticals is limited by the use oforganic solvent.

This mechanism is proposed to proceed by ring slippage. First, reduction and carbonylation of the pertechnetate/perrhenate with CrCl₃ and/or Cr(CO)₆ to from the 6 coordinate intermediate. Subsequent reaction with the substituted ferrocene through ring-slipped, bridged intermediates then gives product. The transfer of the more electron deficient ring is favored by the stabilization of thetransition state of η⁵- η³ ring slip of ferrocene.

Aqueous synthesis enables development for medically relevant radiopharmaceuticals. First aqueous synthesis offac-[^99mTc(η⁵ -Cp-C(O)CH₃)(CO)₃] was described by the Alberto lab utilized a metal-mediated retroDiels-Alder to synthesize the organotechnetium complexes.^[14]

In a step-wise manner, the carboxylate first coordinates to technetium followed by coordination to the adjacent cyclopentadiene (Path A). The reaction is thermodynamically driven, given a strong electronic interaction between [^99mTc(CO)₃]⁺ and thecyclopentadiene.

The favorable formation of the {(η⁵-Cp)Tc} as a driving force for formation of the product 2, prompted the use of the Diels-Ader dimer (HCp-COOH)₂ (Thiele’s acid) as a precursor to the cyclopentadiene. Thermal cracking of 3 typically requires T >160 °C. Reaction of 3 and 1 at 95 °C for 30 min in buffer gave quantitative formation of 2. As no free HCp-COOH was observed, in situ retro Diels-Alder and subsequent entry into path A was excluded.

The metal-mediated retroDiels-Alder reaction suggests a general approach to [(Cp-R)^99mTc(CO)₃], enable access to a variety of R groups on the Cp ring.

With the development of this retro Diels-Alder method for synthesis of^99mTc and Re complexes in aqueous media by the Alberto lab, The labeling of biomolecules with piano-stool like complexes is now possible. Enabling access to the development of novel radiopharmaceuticals.

Technetium has been shown to react similarity toosmium. Able to catalyze a cisdihydroxylation.

• Organometallic compounds