With an aim of developing a bacteria-specific molecular imaging agent, ciprofloxacin has been modified with a propylamine spacer and linked to two common bifunctional chelators, p-SCN-Bz-DOTA and p-SCN-Bz-NOTA. The two ciprofloxacin conjugates, CP-PA-SCN-Bz-DOTA (1) and CP-PA-SCN-Bz-NOTA (2), were radiolabeled with (68)Ga in >90% radiochemical yield and were moderately stable in vitro for 4 h. The efficacy of (68)Ga-1 and (68)Ga-2 has been investigated in vitro in Staphylococcus aureus cells where bacterial binding of the radiotracers (0.9-1.0% for (68)Ga-1 and 1.6-2.3% for (68)Ga-2) could not be blocked in the presence of excess amount of unlabeled ciprofloxacin. However, uptake of radiotracers in live bacterial cells was significantly higher (p < 0.01) than that in non-viable bacterial cells. Bacterial infection targeting efficacy of (68)Ga-1 and (68)Ga-2 was tested in vivo in rats where the infected muscle-to-inflamed muscle ((68)Ga-1: 2 ± 0.2, (68)Ga-2: 3 ± 0.5) and infected muscle-to-normal muscle ratios ((68)Ga-1: 3 ± 0.4, (68)Ga-2: 6.6 ± 0.8) were found to improve at 120 min p.i. Fast blood clearance and renal excretion was observed for both the radiotracers. The two (68)Ga-labeled infection targeting radiotracers could discriminate between bacterial infection and inflammation in vivo and are worthy of further detailed investigation as infection imaging agents at the clinical level.

68Ga-PET has emerged as an important diagnostic tool for precise detection and monitoring of oncological situations. Availability, cost, and radiosynthesis procedure are determining steps for success of a radioisotope/radiopharmaceutical in nuclear medicine. Availability of 68Ga from a 68Ge/68Ga generator containing a long-lived parent radioisotope (68Ge: t 1/2 = 271 days) and an inexpensive, simplified production of 68Ga-radiopharmaceuticals through kit methodology has allowed smooth accommodation of 68Ga-PET in clinics. The uncomplicated formulation of 68Ga-radiopharmaceuticals from a lyophilized, cold kit is an impending breakthrough in clinical PET. The huge success of 68Ga in neuroendocrine tumor and prostate cancer imaging along with the regulatory approval of respective cold kits has opened a pathway for development of kits for other evolving radiotracers. There is a definite scope for increased participation of commercial manufacturers and distributors of cold kits to spread the potential of 68Ga worldwide across all the geographical locations and satellite centers.

Peptides containing RGD and NGR motifs display high affinity towards tumor vasculature molecular markers, integrin αβ and CD13 receptors, respectively. In the present study, RGD and NGR peptides were conjugated with the novel acyclic chelator ,'-bis-[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-,'-diacetic acid (HBED-CC) for radiolabeling with Ga. The radiotracers [Ga-HBED-CC-c(NGR)] and [Ga-HBED-CC-c(RGD)] were quite hydrophilic with respective log values being -2.8 ± 0.14 and -2.1 ± 0.17.Ga-HBED-CC-c(RGD) displayed a significantly higher ( < 0.05) uptake in murine melanoma B16F10 tumors as compared to Ga-HBED-CC-c(NGR) indicating its higher specificity towards integrin αβ-positive tumors. The two radiotracers showed similar uptake in CD13-positive human fibrosarcoma HT-1080 tumor xenografts (∼1.5 ± 0.2% ID g). The tumor uptake of the two radiotracers was significantly reduced ( < 0.05) in both animal models during blocking studies. The tumor-to-blood ratio was observed to be ∼2-2.5 for the two radiotracers, whereas the tumor-to-muscle ratio was significantly higher ( < 0.005) for Ga-HBED-CC-c(RGD) in the two animal models. The two radiotracersGa-HBED-CC-c(NGR) and Ga-HBED-CC-c(RGD) exhibited renal excretion with rapid clearance from blood and other non-target organs. Thus,Ga-chelated HBED-CC conjugated NGR and RGD peptides expressed features conducive towards development as tumor targeted molecular imaging probes. This study further opens avenues for the successful conjugation of different peptides with the acyclic chelator HBED-CC and expansion of Ga-based radiopharmaceuticals.

The biological behavior of Ga-based radiopharmaceuticals can be significantly affected by the chelators' attributes (size, charge, lipophilicity). Thus, this study aimed at examining the influence of three different chelators, DOTAGA, NODAGA, and HBED-CC on the distribution pattern of Ga-labeled NGR peptides targeting CD13 receptors. Ga-DOTAGA-c(NGR), Ga-NODAGA-c(NGR), and Ga-HBED-CC-c(NGR) were observed to be hydrophilic with respective log p values being -3.5 ± 0.2, -3.3 ± 0.08, and -2.8 ± 0.14. The three radiotracers exhibited nearly similar uptake in human fibrosarcoma HT-1080 tumor cells with 86%, 63%, and 33% reduction during blocking studies with unlabeled cNGR peptide for Ga-DOTAGA-c(NGR), Ga-NODAGA-c(NGR), and Ga-HBED-CC-c(NGR), respectively, indicating higher receptor specificity of the first two radiotracers. The neutral radiotracer Ga-NODAGA-c(NGR) demonstrated better target-to-non-target ratios during in vivo studies compared to its negatively charged counterparts, Ga-DOTAGA-c(NGR) and Ga-HBED-CC-c(NGR). The three radiotracers had similar HT-1080 tumor uptake and being hydrophilic exhibited renal excretion with minimal uptake in non-target organs. Significant reduction (p< .005) in HT-1080 tumor uptake of the radiotracers was observed during blocking studies. It may be inferred from these studies that the three radiotracers are promising probes for in vivo imaging of CD13 receptor expressing cancer sites; however, Ga-NODAGA-c(NGR) is a better candidate.