(68)Ga-radiopharmaceuticals for PET imaging of infection and inflammation.

Infection imaging has been challenging over the past four decades, which provided an excellent playing field for researchers working in this area, and till date the quest continues to find an ideal imaging agent. Labelled leukocytes were first developed in the 1970s for imaging infection lesions such as osteomyelitis, cellulitis, diabetic foot, Crohn's disease, inflammatory bowel disease, fever of unknown origin, etc. Subsequently labelled antibiotics such as (99m)Tc-labelled ciprofloxacin have emerged for directly identifying live bacterial infections. From the early 1970s through the mid-1980s,( 67)Ga-Citrate was the prime radionuclide for imaging of inflammation and infection of musculoskeletal origin. Although (68)Ga-PET was described in 1960s for tumour imaging, recent reports described (68)Ga-Citrate and (68)Ga-transferrin as possible agents for PET-imaging of infection due to successful application of (67)Ga-Citrate SPECT in the past, despite its limitations. It is important to establish a faster imaging method for (68)Ga, as its half-life is 68 min compared to 78.3 hrs for (67)Ga. Preparation of (68)Ga-Citrate and (68)Ga-transferrin is described, with very high yield and high radiochemical purity (RCP), which is ideally suited for routine clinical studies. Biodistribution of (68)Ga-Citrate-PET images were characterised with high blood pool, high liver and bone (growth plate) uptake with low soft-tissue activity. (68)Ga-Citrate or (68)Ga-transferrin was able to detect infected lesions in rats within 5-10 min post injection but a focal intense uptake at the lesion (SUV(max)) was visualized only at 30 min, which increased for up to 6 hrs post injection with concomitant decrease in the cardiac blood pool activity. The liver and bowel activity decreased after 90 min then stabilised. In the patient studies, infection lesions were detected within 30 min post injection of (68)Ga-Citrate. Cardiac blood pool and liver activities decreased during the period of study. Interestingly, there was persistent high vascular activity in the thigh region. One of the major limitations of (67)Ga-Citrate SPECT is the delayed post injection waiting time of 48 hrs, in contrast to 60 min post injection waiting with (68)Ga-Citrate. The distinct difference in imaging time is intriguing, although there is no chemical difference between (67)Ga-Citrate and (68)Ga-Citrate, except for the radiolabel. No literature is available on early imaging times using (67)Ga-SPECT. When compared (68)Ga/(67)Ga-Citrate images at 60 min post injection in normal rats, (68)Ga-PET showed better images with low background activity than (67)Ga-SPECT agent. This may be due to short half-life of (68)Ga (68 min), as it would have decayed one half-life at 60 min post-imaging time, compared to the SPECT agent ((67)Ga), which would require 76 hrs to undergo one half-life. Therefore, the visual difference in background can be attributed to the difference in the half-lives of these two agents. Similarly, uptake of (68)Ga by liver, cardiac blood pool activity is much lower than (67)Ga at 60 min post injection period, may be attributed to the faster decay of (68)Ga than (67)Ga. High background activity of (68)Ga-Citrate in the thorax and upper abdomen at 60 min post-injection may interfere with detecting lesions in these regions; therefore, (68)Ga-PET is more suitable for imaging lesions in the lower abdomen and the extremities. The short half-life of (68)Ga (68 min) may be advantageous from low dosimetry to the patients, but disadvantageous for longer periods of study. Since (68)Ga-Citrate was capable of detecting infection within 60 min, the need for imaging for longer periods may not be warranted. The functional imaging was not limited to diagnosing infection but it could be extended to surgical planning and antibiotic therapy monitoring of osteomyelitis and in distinguishing prosthetic infection from loosening of prosthesis. (18)F-FDG is sensitive but has the limitation of giving false positive results in patients with bone prosthesis, even if there is no infection or mobilisation. But the available literature clearly indicated (68)Ga-Citrate was positive only in cases of infection. In summary, preliminary reports suggest (68)Ga-Citrate PET/CT is useful in the diagnosis of suspected bone infections with reliable sensitivity, specificity, positive predictive value, negative predictive value and overall accuracy. Preliminary reports with (68)Ga-Transferrin showed it is capable of detecting both Gram-positive Staphylococcus aureus (Staph A) and Gram-negative Proteus mirobilis. This is an incidental finding but gives an insight into the potential of this agent to detect more than one bacterial infection.

(68)Ga-Citrate-PET for diagnostic imaging of infection in rats and for intra-abdominal infection in a patient.

OBJECTIVES: 67Ga-Citrate has been extensively used for infection and inflammation imaging for the past four decades but has limitations. In the present study, we explored the ability of 68Ga-Citrate to detect Staphylococcus aureus (Staph A) infection in rats and further studied its ability to localize intra-abdominal infection in a patient. METHODS: An infection was induced in male Wistar rats by injecting Staph A in the right thigh muscle. In this study a simple method was described for the preparation of 68Ga-Citrate with > 99% yield and purity. 68Ga-Citrate (15 MBq/rat and 150 MBq/patient) was injected intravenously and the images were acquired for 10 min each. RESULTS: 68Ga-Citrate uptake was moderate at the infection lesion within 5 min post injection but intense focal uptake was visualized from 30 min to 6 hr post-injection in rats. Cardiac blood pool and liver activity decreased during the same period of study. In the patient studied, an infected area in the abdomen at the site of recent appendectomy was detected within 30min post-injection of 68Ga-Citrate, which was consistent with CT and microbiology findings. CONCLUSION: A simple method of preparation of 68Ga-Citrate with > 99% yield and purity was described, suitable for routine clinical work. Our results showed 68Ga-Citrate is capable of detecting Staph A infection in rats and an intraabdominal infection in a post-operative patient. These findings indicate the high potential of 68Ga-Citrate for clinical utility.

Potential use of 68Ga-apo-transferrin as a PET imaging agent for detecting Staphylococcus aureus infection.

INTRODUCTION: (67)Ga citrate has been extensively used to detect infection and inflammation since 1971. However, its clinical utility is compromised due to several limitations. The present project explored whether (68)Ga-apo-transferrin ((68)Ga-TF), when prepared in vitro, is a useful agent for positron emission tomography (PET) imaging of bacterial infection. METHODS: An infection was induced in male Wistar rats by injecting 5 × 10(5) CFU units of Staphyococcus aureus in the right thigh muscle. (68)Ga-TF was synthesized by mixing (68)GaCl(3) with apo-transferrin (TF, 2 mg) in sodium carbonate (0.1 M, pH 7.0) and incubating at 40 °C for 1 h. Animals were injected with 10-15 MBq of (68)Ga-TF containing approximately 0.2 mg TF and imaged at different time intervals using Siemens Biograph PET-CT. RESULTS: When (68)Ga-TF were injected in the infected rats, the infection lesion was detectable within 20 min post injection. The biodistribution showed the uptake at the lesion increased with time as shown by significantly increased standard uptake values for up to 4 h post injection. There was a considerable decrease in the background activity during the same period of study, giving higher target-to-muscle ratios. Blood pool activity at 3 h post injection was insignificant. (68)GaCl(3) (when not conjugated to TF) did not localize at the infection lesion up to 120 min post injection. CONCLUSION: The preliminary results suggest that (68)Ga-TF is capable of detecting S. aureus infection in the rat model, within an hour after intravenous injection.