[68Ga]/[188Re] Complexed [CDTMP] Trans-1,2-Cyclohexyldinitrilotetraphosphonic Acid As a Theranostic Agent for Skeletal Metastases

Abstract

Objective: Metastasis of the osseous tissue is one of the frequent and severe aggravations as a result of several neoplastic conditions, such as metabolic disorders, infections, and cancer. The objective of this study was to evaluate the pertinence of [⁶⁸Ga]-trans-1,2-cyclohexyldinitrilo tetramethylene phosphonic acid (CDTMP) as a potential bone imaging agent for positron emission tomography (PET) applications as well as to assess [¹⁸⁸Re]-CDTMP for bone pain palliation in metastatic skeletal disorders.

Methods: ⁶⁸Ga complex of CDTMP was prepared at 80°C at pH 3.5, and ¹⁸⁸Re complex of CDTMP was prepared at room temperature. [⁶⁸Ga]-CDTMP complex was investigated as PET tracer while the therapeutic efficacy was assessed for [¹⁸⁸Re]-CDTMP. Labeling efficiency, biodistribution, myelotoxicity, and imaging studies were carried out for the complexes synthesized. Both PET and MicroPET imaging studies were performed for [⁶⁸Ga]-CDTMP whereas SPECT acquisitions were acquired for [¹⁸⁸Re]-CDTMP. Data were analyzed semiquantitatively for all the scintigraphic scans obtained.

Results: The radiolabeling efficiency was observed to be >70% for [⁶⁸Ga]-CDTMP. High bone uptake of [⁶⁸Ga]-CDTMP as compared to contralateral tissue was found in PET imaging in Balb/C mice and New Zealand rabbit; the similar result for bone uptake was correlated in the biodistribution study of the compound in BALB/c mice at different time intervals. Biodistribution experiments carried out in mice showed maximum uptake of 6.12 ± 1.22%ID/g at 45 min postinjection. For [¹⁸⁸Re]-CDTMP, total skeletal uptake was 8.12 ± 1.11%ID/g observed at 1 h postinjection from biodistribution data. High renal uptake confirms renal route of excretion. A good hydroxyapatite binding too was seen for both the complexes. No evidence of destruction or adverse functioning of vital organs was observed for the ¹⁸⁸Re complex.

Conclusion: [⁶⁸Ga]-CDTMP complex can be used as a promising PET bone imaging agent and [¹⁸⁸Re]-CDTMP as a surrogate moiety for therapeutic application. Owing to the short half-life of ⁶⁸Ga (68 min), cyclotron-independent radiopharmacy, fast clearance, and rapid renal excretion as evidenced in preclinical animal models. Very low myelotoxicity and highly selective bone uptake prove the potential of [¹⁸⁸Re]-CDTMP for therapeutic application.

Keywords: 188Re; 68Ga; CDTMP; positron emission tomography imaging; radionuclide; radiopharmaceutical.

Figure 1

Chemical structure of CDTMP.

Figure 2

Optimization of radiolabeling of [⁶⁸Ga]-CDTMP for (A) pH, (B) temperature, (C) heating time, and (D) compound concentration.

Figure 3

Percentage intact ligand as a function of time showing human serum stability of [⁶⁸Ga]-CDTMP at physiological conditions.

Figure 4

Time activity curve showing blood clearance of [⁶⁸Ga]-CDTMP (20 MBq) postinjection in New Zealand rabbit.

Figure 5

(A) [⁶⁸Ga]-CDTMP anterior view 45 min p.i. (B) [⁶⁸Ga]-CDTMP posterior view of positron emission tomography (PET) image in normal rabbit 45 min p.i. (C) Sagittal section of PET image. (D) CT transaxial PET transaxial and PET/CT-fused transaxial image confirming bone uptake.

Figure 6

(A) CT frontal view. (B) [⁶⁸Ga]-CDTMP frontal view of MicroPET image in Balb/C mice 45 min postinjection. (C) PET/CT-fused frontal view image. (D) 3D MicroPET/CT (volume rendered CT image) coregistered image confirming bone uptake.

Figure 7

Whole body γ scintigraphy of [¹⁸⁸Re]-CDTMP in rabbits l h postinjection (n = 2).

Figure 8

Biodistribution of [⁶⁸Ga]-CDTMP in Balb/c mice. Data expressed in %ID/g ± SD from five animals.

Figure 9

Biodistribution of [¹⁸⁸Re]-CDTMP in Balb/c mice. Data expressed in %ID/g ± SD from five animals.

Figure 10

(A) Line graph depicting dynamic behavior of [⁶⁸Ga]-CDTMP and [¹⁸⁸Re]-CDTMP in blood and bone tissue in mice. (B) Bone to blood ratio as a function of time for [⁶⁸Ga]-CDTMP. (C) Bone to blood ratio as a function of time for [¹⁸⁸Re]-CDTMP.