Abstract
BackgroundBisphosphonates possess strong affinity to bone. 99mTc bisphosphonate complexes are widely used for bone scintigraphy. For positron emission tomography (PET) bone imaging, Ga-68-based PET tracers based on bisphosphonates are highly desirable.FindingsTwo trimeric bisphosphonate conjugates of the triazacyclononane-phosphinate (TRAP) chelator were synthesized, labeled with Ga-68, and used for microPET imaging of bone in male Lewis rats. Both Ga-68 tracers show bone uptake and, thus, are suitable for PET bone imaging. Surprisingly, Ga-71 nuclear magnetic resonance data prove that Ga(III) is not located in the chelating cavity of TRAP and must therefore be bound by the conjugated bisphosphonate units.ConclusionThe intrinsic Ga-68 chelating properties of TRAP are not needed for Ga-68 PET bone imaging with TRAP-bisphosphonate conjugates. Here, TRAP serves only as a trimeric scaffold. For preparation of Ga-68-based bone seekers for PET, it appears sufficient to equip branched scaffolds with multiple bisphosphonate units, which serve both Ga-68-binding and bone-targeting purposes.
Highlights
Bisphosphonates possess strong affinity to bone. 99mTc bisphosphonate complexes are widely used for bone scintigraphy
The intrinsic Ga-68 chelating properties of TRAP are not needed for Ga-68 positron emission tomography (PET) bone imaging with TRAP-bisphosphonate conjugates
Upon investigation of the mode of gallium binding, we found that an equimolar mixture of 69,71 Ga3+ and either 68 Ga-TRAP(MDP)3 or 68 Ga-TRAP(PDP)3 does not yield any signal in 71 Ga nuclear magnetic resonance (NMR) spectra, not even after heating to 95°C for hours
Summary
Bisphosphonates possess strong affinity to bone. 99mTc bisphosphonate complexes are widely used for bone scintigraphy. 99mTc bisphosphonate complexes are widely used for bone scintigraphy. For positron emission tomography (PET) bone imaging, Ga-68-based PET tracers based on bisphosphonates are highly desirable. Geminal bisphosphonates possess strong affinity to bone [1,2]. Administration of bisphosphonates leads to inhibition of osteoclasts (bone resorbing cells), which results in a lower rate of bone resorption [3,4]. Bisphosphonate complexes of 99mTc (e.g., of medronic acid, ‘99mTc-MDP’; see Figure 1) are the mainstay of bone imaging by scintigraphy and SPECT. As positron emission tomography (PET) offers higher resolution and sensitivity, PET bone-imaging agents are of high interest.
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