Novel Radiolabeled Bisphosphonates for PET Diagnosis and Endoradiotherapy of Bone Metastases

Abstract

Bone metastases, often a consequence of breast, prostate, and lung carcinomas, are characterized by an increased bone turnover, which can be visualized by positron emission tomography (PET), as well as single-photon emission computed tomography (SPECT). Bisphosphonate complexes of 99mTc are predominantly used as SPECT tracers. In contrast to SPECT, PET offers a higher spatial resolution and, owing to the 68Ge/68Ga generator, an analog to the established 99mTc generator exists. Complexation of Ga(III) requires the use of chelators. Therefore, DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), NOTA (1,4,7-triazacyclododecane-1,4,7-triacetic acid), and their derivatives, are often used. The combination of these macrocyclic chelators and bisphosphonates is currently studied worldwide. The use of DOTA offers the possibility of a therapeutic application by complexing the β-emitter 177Lu. This overview describes the possibility of diagnosing bone metastases using [68Ga]Ga-BPAMD (68Ga-labeled (4-{[bis-(phosphonomethyl))carbamoyl]methyl}-7,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododec-1-yl)acetic acid) as well as the successful application of [177Lu]Lu-BPAMD for therapy and the development of new diagnostic and therapeutic tools based on this structure. Improvements concerning both the chelator and the bisphosphonate structure are illustrated providing new 68Ga- and 177Lu-labeled bisphosphonates offering improved pharmacological properties.

Syntheses and evaluation of 68Ga‐ and 153Sm‐labeled DOTA‐conjugated bisphosphonate ligand for potential use in detection of skeletal metastases and management of pain arising from skeletal metastases

“…However, the systematic comparative evaluation showed that when 153 Sm was used as the radiometal, there was no significant improvement of skeletal accumulation of the DOTA‐Bn‐SCN‐BP complex over its DOTMP complex as the later demonstrated optimal properties required for an agent for bone pain palliation. However, recent reports have shown that modifications in the side chains of the central carbon atom of the bisphosphonate moiety such as introduction of a hydroxyl group (DOTA‐conjugated α‐OH‐bisphosphonate) and an aromatic nitrogen atom (DOTA‐Zoledronic acid) lead to higher bone accumulation due to increased affinity for bone material as compared to simple DOTA‐coupled bisphosphonate …”

“…It was envisaged that the affinity of the radiotracer for bone and particularly for metastatic skeletal lesion sites could be enhanced by coupling bisphosphonate with a suitable bifunctional chelator (BFC) for complexing 68 Ga, such that the bisphosphonate moiety is free for binding with HA on the bone surface. In recent years, the syntheses and evaluation of a number of 68 Ga‐complexes of BFC‐bisphosphonate conjugates using DOTA (1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetic acid) and NOTA (1,4,7‐triazacyclododecane‐1,4,7‐triacetic acid) derivatives have been reported . This concept of using BFC‐bisphosphonate conjugate for efficient targeting of skeletal metastases has also been successfully used for the palliative care of pain arising from skeletal metastases with therapeutic radionuclides …”

Molecular Imaging with 68Ga Radio-Nanomaterials: Shedding Light on Nanoparticles

“…68 Ga-citrate has been utilized to image infection in animal models and human patients [38,39]. 68 Ga-phosphonate complexes have served as bone metastases trackers in small animal models [40,41]. A derivative of tris(salicylaldimine), Tris(4,6-dimethoxysalicylaldimine)-N,N -bis(3-aminopropyl)-N,N -ethylenediamine (BAPEN), may be used as cardiac function radiotracer when radiolabeled with 68 Ga, forming 68 Ga-BAPEN [42,43].…”

[177Lu]Lu-DOTA-ZOL Bone Pain Palliation in Patients with Skeletal Metastases From Various Cancers: Efficacy and Safety Results

“…For bone pain palliation it has been labelled with several bisphosphonates such as ethylene diamine tetramethylene phosphonic acid (EDTMP) [7 -9], (4-{[(bis(phosphonomethyl)) carbamoyl]methyl}-7,10-bi (carboxymethyl)-1,4,7,10-tetraazacyclododec-1-yl) acetic acid (BPAMD) [10][11][12][13][14][15] Zoledronate (DOTA-ZOL) [16][17][18][19][20][21][22], and DOTMP [23,24]. Zoledronic acid, compared to EDTMP and DOTMP, has signi cantly higher hydroxyapatite binding and better internalization by osteoclasts.…”

“…These superior antiresorptive properties lead to increased apoptosis [25]. DOTA-ZOL can be labelled with both 68 Ga and 177 Lu to form a theranostic pair [19]. However, only two studies have reported its safety from the dosimetric aspects [26,27].…”