Yttrium-90 and Rhenium-188 Radiopharmaceuticals for Radionuclide Therapy

Despite the proven clinical success of 99m Tc/ 188/186 Re bisphosphonates,
these radiopharmaceuticals are far from optimal, from the chemical and
pharmaceutical points of view. For example, despite decades of clinical use, their
structures and compositions remain unknown. A critical review of the literature
reveals that the 99m Tc MDP preparation used in clinical practice is composed of a
mixture of anionic polymers of different properties [13.5]. A particular concern is
that the in vivo stability of 186/188 Re bisphosphonates does not adequately match
their physical half-lives, and a large fraction of the injected complex degrades to
perrhenate in vivo within 24 h, leading to reduced bone uptake and higher soft
tissue doses [13.6]. Furthermore, 186/188 Re bisphosphonates are not chemically
analogous to their technetium counterparts and do not target bone metastases
unless additional ‘carrier’ non-radioactive rhenium is added [13.7]. Consequently,
there is a need for rational design of 186/188 Re labelled bisphosphonate derivatives
to improve specificity and reduce soft tissue and bone marrow doses during
radionuclide therapy.
In current technetium rhenium bisphosphonate complexes, the
bisphosphonate acts as both the chelator and the targeting group. Each role,
however, may compromise the other because bisphosphonates are excellent bone
seeking agents but poor rhenium chelators. To improve upon current 186/188 Re
bisphosphonates, a more logical approach is the use of targeted bifunctional
ligands in which the targeting (bisphosphonate) and metal chelating groups are
separated within the molecule so that they can each function independently
and effectively. A few recent reports describe such a bisphosphonate chelator
bifunctional approach [13.8, 13.9]. These bisphosphonate conjugates, however,
require complicated multistep synthetic strategies, show high plasma protein
binding and often form enantiomeric mixtures. Herein reported, is a new chelator
bisphosphonate conjugate 3 (DPA bisphosphonate) that is synthesized using
mild aqueous conditions in one step from commercially available compounds.
In addition, 3 efficiently complexes with the M(CO) 3 + core 4 (M = Tc, Re) to
form single, well defined isostructural technetium rhenium complexes 5 and 6
with no detectable protein binding that efficiently accumulate in bone tissue in
vivo. A second new chelator 7 (DTC bisphosphonate) is herein reported, which
comprises a dithiocarbamate linked to a bisphosphonate group, which forms a
stable complex with the 99m Tc(V) nitride core 8 to give a bis(bisphosphonate)
complex 9 that also accumulates efficiently in bone in vivo.
Our approach requires the bisphosphonate part of the molecule to be
separated from the chelator by a spacer, to avoid any bisphosphonate–metal
interactions. In addition, the radionuclide must selectively coordinate with the
chelating group, not the bisphosphonate, and must remain inert under in vivo
conditions. The organometallic precursor fac-[M(CO) 3 (H 2 O) 3 ] + (M = Tc, Re)
(4, see Fig. 13.1), pioneered by Jaouen et al. and Alberto et al., facilitates the
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