Dataset Information

Bone targeting compounds for radiotherapy and imaging: *Me(III)-DOTA conjugates of bisphosphonic acid, pamidronic acid and zoledronic acid.

ABSTRACT: Background:Bisphosphonates have a high adsorption on calcified tissues and are commonly used in the treatment of bone disorder diseases. Conjugates of bisphosphonates with macrocyclic chelators open new possibilities in bone targeted radionuclide imaging and therapy. Subsequent to positron emission tomography (PET) examinations utilizing 68Ga-labelled analogues, endoradiotheraphy with 177Lu-labelled macrocyclic bisphosphonates may have a great potential in the treatment of painful skeletal metastases. Methods:Based on the established pharmaceuticals pamidronate and zoledronate two new DOTA-?-OH-bisphosphonates, DOTAPAM and DOTAZOL(MM1.MZ) were successfully synthesized. The ligands were labelled with the positron emitting nuclide 68Ga and the ?- emitting nuclide 177Lu and compared in in vitro studies and in ex vivo biodistribution studies together with small animal PET and single photon emission computed tomography (SPECT) studies against [18F]NaF and a known DOTA-?-H-bisphosphonate conjugate (BPAPD) in healthy Wistar rats. Results:The new DOTA-bisphosphonates can be labelled in high yield of 80 to 95 % in 15 min with post-processed 68Ga and >98 % with 177Lu. The tracers showed very low uptake in soft tissue, a fast renal clearance and a high accumulation on bone. The best compound was [68Ga]DOTAZOL (SUV Femur?=?5.4?±?0.6) followed by [18F]NaF (SUV Femur?=?4.8?±?0.2), [68Ga]DOTAPAM (SUV Femur?=?4.5?±?0.2) and [68Ga]BPAPD (SUV Femur?=?3.2?±?0.3). [177Lu]DOTAZOL showed a similar distribution as the diagnostic 68Ga complex. Conclusion:The 68Ga labelled compounds showed a promising pharmacokinetics, with similar uptake profile and distribution kinetics. Bone accumulation was highest for [68Ga]DOTAZOL, which makes this compound probably an interesting bone targeting agent for a therapeutic approach with 177Lu. The therapeutic compound [177Lu]DOTAZOL showed a high target-to-background ratio. SPECT experiments showed concordance to the PET scans in healthy rats. [68Ga/177Lu]DOTAZOL appears to be a potential theranostic combination in the management of disseminated bone metastases.

SUBMITTER: Meckel M

PROVIDER: S-EPMC5843815 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:PurposeBariatric surgery is an effective treatment for severe obesity but causes substantial bone loss and increased risk of fractures. To date, there have been no studies examining whether pharmacologic treatments can prevent bone loss after bariatric surgery. We performed an exploratory study to examine the preliminary safety and efficacy of zoledronic acid (ZOL), a potent anti-resorptive bisphosphonate, to suppress bone turnover markers (BTM) and prevent declines in bone mineral density (BMD) after Roux-en-Y gastric bypass (RYGB) surgery.MethodsWe performed an open-label pilot study of pre-operative ZOL in postmenopausal women with obesity who were planning RYGB (n = 4). A single dose of zoledronic acid 5 mg was given intravenously prior to RYGB. Serum bone biochemistries including C-telopeptide (CTX) and procollagen type 1 N-terminal propeptide (P1NP) were measured at multiple timepoints throughout the 24-week study. BMD was also obtained at the spine and hip by dual-energy x-ray absorptiometry (DXA) and at the trabecular spine by quantitative computed tomography (QCT) at pre-operative baseline and 24 weeks. Results were compared against pre-operative baseline and against changes among RYGB historical controls (n = 10).ResultsAt 2 weeks after RYGB, there was a nonsignificant trend for CTX and P1NP levels to be lower than baseline levels in the ZOL group. By 24 weeks after RYGB, however, participants who received ZOL had a significant increase in CTX above pre-operative baseline (+0.228 ± 0.117 ng/dL, p = 0.030) but this CTX rise was less than that observed in the controls (+0.601 ± 0.307 ng/dL, p = 0.042 between groups). Despite ZOL use, participants had significant areal BMD loss at the total hip as compared to pre-operative baseline (-4.2 ± 1.5%, p = 0.012) that was similar in magnitude to total hip BMD loss in the controls (-5.5 ± 3.9%, p = 0.005). There was a suggestion that the ZOL group might be protected against trabecular spine volumetric bone loss as compared to the control group (+4.8 ± 8.0% vs. -5.9 ± 7.0%, p = 0.075 between groups). Serum calcium, 25-hydroxyvitamin D, and parathyroid hormone did not change in either group. No hypocalcemia or serious adverse events were reported after ZOL.ConclusionIn this proof of concept study, a single dose of ZOL prior to RYGB appeared to transiently mitigate but not fully prevent high bone turnover in the acute postoperative period. At 24 weeks after RYGB, our preliminary data suggest that ZOL was not sufficient to prevent bone loss at the hip, although it may preserve bone density at the trabecular spine. Further prospective, controlled studies are needed to confirm our findings and to identify the best strategies for preventing bone loss in bariatric patients receiving RYGB.

Dataset Information

Bone targeting compounds for radiotherapy and imaging: *Me(III)-DOTA conjugates of bisphosphonic acid, pamidronic acid and zoledronic acid.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets