The “Carbonyl Story” and Beyond; Experiences, Lessons and Implications

Abstract

The complex [ 99m Tc(OH 2) 3 (CO) 3 ] + has become a versatile building block in radiopharmaceutical chemistry, applied by many groups worldwide. However, despite widespread efforts, only one compound has made it right the way through clinical trials. Along the way from its discovery to its development into an eventual product, the author experienced issues that he would handle differently in retrospect. In this article, these experiences are turned into "lessons" that might be helpful for young researchers finding themselves in similar situations. Beside issues with patenting and company strategies, the carbonyl story has provided scientific implications beyond its own story, and insights from which any future 99m Tc-based chemistry for radiopharmacy or molecular imaging might benefit. Carbon monoxide complexes are not a class of compounds one would immediately relate to imaging agents with short-lived radionuclides such as 99m Tc (t 1/2 = 6 h). As they are typically prepared under high pressure/high temperature conditions and in organic solvents, their syntheses seem to contradict any preparative requirements for routine application in hospitals. Indeed, such CO complexes were not supposed to find any application in the beginning, when the main question was about how to prepare complexes with the fac-[ 99 Tc(CO) 3 ] + core at ambient CO pressure. The question arose from the chase to the still elusive complex [Cp* 99 TcO 3 ], a homologue of the wellknown [Cp*ReO 3 ] (Cp* = [C 5 Me 5 ] À). [1] [ 99 Tc 2 (CO) 10 ] was prepared by an adapted rhenium synthesis [2] under medium-high pressure conditions at Los Alamos National Laboratory in Sattelberger's group. This method could though not be pursued in our labs since reactions in autoclaves with radioactive materials were not allowed. The other medium CO pressure synthesis by Knight et al. to Tc 2 (CO) 10 was also not appropriate for the same reasons. [3] Challenged by the fundamental question to prepare fac-[ 99 Tc(CO) 3 ] +-type complexes at ambient CO pressure, we bypassed 99 Tc 2 (CO) 10 and found a direct path to [ 99 TcCl 3 (CO) 3 ] 2À directly from [ 99 TcO 4 ] À or [ 99 TcOCl 4 ] À. [4] Subjecting many reductants to the reaction of [ 99 TcO 4 ] À to carbonyls, borane H 3 B•THF turned out to be the reductant of choice. This purely fundamental 99 Tc chemistry did not imply its use in radioimaging agents at all. This vista turned when we stated excellent water solubility and stability of [ 99 TcCl 3 (CO) 3 ] 2À or whatever formed from it in solution. We identified this compound as [ 99 Tc(OH 2) 3 (CO) 3 ] + , an organometallic semi-aquaion, as we termed it. Educated in the spirit of "no water/no air" in organometallic chemistry we learned in lesson 1 that [a

[Tc(OH2)(CO)3(PPh3)2]+: A Synthon for Tc(I) Complexes and Its Reactions with Neutral Ligands

“…37 Particularly the latter compound seems to be interesting for nuclear medical considerations, since it belongs to the family of tricarbonyltechnetium (I) complexes, that originates from the (structurally not yet fully characterized) [Tc(CO) 3 (OH 2 ) 3 ] + cation. 38 In contrast to the analogous rhenium cation 39,40 and despite several attempts, [Tc(CO) 3 (OH 2 ) 3 ] + has not yet been characterized crystallographically. Several pH-dependent protonation/condensation and ligand exchange reactions are expected for aqua complexes of technetium, as has been found for the corresponding [Re(CO) 3 (OH 2 ) 3 ] + cation.…”

“…This involves the Tc­(III) cation [TcCl 2 ­(OH 2 )­(tacn)] + (tacn = 1,3,6-triazacyclononane), a cationic Tc­(I) complex with DPPE (DPPE = 1,2-bis­(diphenylphosphino)­ethane), and a neutral tricarbonyltechnetium­(I) complex . Particularly the latter compound seems to be interesting for nuclear medical considerations, since it belongs to the family of tricarbonyltechnetium­(I) complexes, that originates from the (structurally not yet fully characterized) [Tc­(CO) 3 ­(OH 2 ) 3 ] + cation . In contrast to the analogous rhenium cation , and despite several attempts, [Tc­(CO) 3 ­(OH 2 ) 3 ] + has not yet been characterized crystallographically.…”

Tricarbonylrhenium(I) and ‐technetium(I) Complexes with Tris(1,2,3‐triazolyl)phosphine Oxides

“…Stable and kinetically inert tricarbonyl complexes of rhenium and technetium are of ongoing interest for the development of novel radiopharmaceuticals for diagnostics and therapy [1–9] . The metastable nuclear isomer 99m Tc is still the ‘workhorse’ in diagnostic nuclear medicine with some 40 million annual administrations worldwide, [10] and rhenium possesses two β − ‐emitting isotopes suitable for therapy: 186 Re and 188 Re.…”

“…For both elements, normal pressure syntheses have been developed for corresponding [M(CO) 3 (H 2 O) 3 ] + (M= 99m Tc, 188 Re) cations, which are perfect precursors for nuclear medical preparations [11,12] . The stability of the formed complexes is mainly governed by the denticity of used ligands, [13] which directed the focus of interest preferably to tridentate ligand systems [1,4,14–20] . This includes pseudotripodal systems such as cyclopentadienyl ligands [21–26] .…”

Should You Become a Chemist Entrepreneur?

“…The examples from biomedical research are especially challenging to commercialize because they require expensive clinical trials . The stories behind these efforts are testaments to persistence as well as creativity, and I highly recommend that anyone considering entrepreneurial efforts read these accounts. − Some of the researchers involved were given university funding, whereas others raised money from investors early on or simply licensed their IP to companies without much help from federal grants or from their universities. As mentioned above, the U.S. encourages commercialization of inventions funded by the federal government, as do some European countries, but many countries do not have extensive programs that fund entrepreneurial efforts.…”