**2.3.2 [18F]Flutemetamol (3'-[18F]F-PiB or [18F]GE067)**

[18F]Flutemetamol (3'-[18F]F-6-OH-BTA1) is an 18F-labeled thioflavin analog of [11C]PiB licensed to GE Healthcare (Koole, et al., 2009). Due to its longer physical half-life in comparison to its parent molecule, [18F]flutemetamol can potentially have a larger impact in clinical and research settings. Unlike other 18F-labeled Aβ PET radiotracers, [18F]flutemetamol has the advantage that there has been extensive work done on its parent molecule, [11C]PiB, which can easily lend itself to the validation of [18F]flutemetamol. Although [11C]PiB and [18F]flutemetamol exhibit similarities in structure, the two radiotracers have slightly different properties. Fortunately, pre-clinical studies of [18F]flutemetamol have demonstrated favorable brain kinetics, good penetration of intact blood-brain barrier (BBB), and fairly rapid washout of non-specific binding (Nelissen, et al., 2009). [18F]Flutemetamol has showed a good safety profile and biodistribution (Koole, et al., 2009). The average typical administered dose is 121 MBq (range=96-147 MBq; 2.59-3.98 mCi) (Koole, et al., 2009); It is important to note that [18F]flutemetamol delivers an effective dose that is 1.7 times larger than that for [11C]PiB (2.37 mSv versus 4.12 mSv) (O'Keefe, et al., 2009); this higher radiation burden is due to the relatively greater radiation dose associated with fluorine-18 (whole-body effective dose conversion factor= 33.6 μSv/MBq for [18F]flutemetamol versus 4.74±0.8 μSv/MBq for [11C]PiB). Nevertheless, there have been no adverse events reported for the use of this radiotracer and, therefore, it has been deemed safe for use in humans (Koole, et al., 2009).

Under the direction of Nelissen and co-workers, [18F]flutemetamol entered Phase I clinical trials in 2009 (Nelissen, et al., 2009). Eight AD patients and 8 healthy controls were used in

dichotomous, with one subset of MCI patients showing abundant "AD-like" neocortical binding ([11C]PiB-positive) and the other subset showing low, non-specific binding ([11C]PiB-negative) (Forsberg, et al., 2008; Okello, et al., 2009; Pike, et al., 2007; Rowe, et al., 2007). As only 40-60% of MCI patients progress to AD, longitudinal studies are needed to determine if this bimodal distribution pattern of [11C]PiB uptake accurately predicts those who will convert to AD (Forsberg, et al., 2008; Kukull, et al., 1990; Okello, et al., 2009; Petersen, et al., 2009). In a study by Forsberg *et al.*, 7 out of 21 tested MCI patients converted to AD after 8.1±6.0 months (Forsberg, et al., 2008). Interestingly, there were detectable group differences between the 7 MCI converters and the 14 non-converters. MCI converters were shown to have lower levels of CSF Aβ1-42 and MMSE test scores compared to non-converters. Additionally, MCI converters were more likely to be ApoE ε4 carriers (85%) than were nonconverters (57%). Most importantly, MCI converters had high [11C]PiB uptake in the frontal, parietal, and temporal cortices and the posterior cingulum, similar to levels in AD patients. Contrastingly, MCI non-converters had significantly lower cortical [11C]PiB retention, indistinguishable from healthy controls. These promising results demonstrate the prognostic

[11C]PiB has now been used in a large number of subjects, consistently showing high sensitivity and specificity in detecting cerebral amyloid deposition *in vivo* with high intraand inter-reader agreement (W. E. Klunk and Mathis, 2008). Due to the short physical halflife of carbon-11 (20.4 minutes), however, [11C]PiB is limited in clinical availability. As a result, Aβ tracers that are radiolabeled with fluorine-18, a radioisotope with a considerably longer half-life (109.4 minutes) than carbon-11, have been developed. Fluorine-18 labeled Aβ PET tracers do not require on-site cyclotrons for their production, thus allowing for a more

[18F]Flutemetamol (3'-[18F]F-6-OH-BTA1) is an 18F-labeled thioflavin analog of [11C]PiB licensed to GE Healthcare (Koole, et al., 2009). Due to its longer physical half-life in comparison to its parent molecule, [18F]flutemetamol can potentially have a larger impact in clinical and research settings. Unlike other 18F-labeled Aβ PET radiotracers, [18F]flutemetamol has the advantage that there has been extensive work done on its parent molecule, [11C]PiB, which can easily lend itself to the validation of [18F]flutemetamol. Although [11C]PiB and [18F]flutemetamol exhibit similarities in structure, the two radiotracers have slightly different properties. Fortunately, pre-clinical studies of [18F]flutemetamol have demonstrated favorable brain kinetics, good penetration of intact blood-brain barrier (BBB), and fairly rapid washout of non-specific binding (Nelissen, et al., 2009). [18F]Flutemetamol has showed a good safety profile and biodistribution (Koole, et al., 2009). The average typical administered dose is 121 MBq (range=96-147 MBq; 2.59-3.98 mCi) (Koole, et al., 2009); It is important to note that [18F]flutemetamol delivers an effective dose that is 1.7 times larger than that for [11C]PiB (2.37 mSv versus 4.12 mSv) (O'Keefe, et al., 2009); this higher radiation burden is due to the relatively greater radiation dose associated with fluorine-18 (whole-body effective dose conversion factor= 33.6 μSv/MBq for [18F]flutemetamol versus 4.74±0.8 μSv/MBq for [11C]PiB). Nevertheless, there have been no adverse events reported for the use of this radiotracer and, therefore, it has been deemed

Under the direction of Nelissen and co-workers, [18F]flutemetamol entered Phase I clinical trials in 2009 (Nelissen, et al., 2009). Eight AD patients and 8 healthy controls were used in

value of [11C]PiB for predicting which MCI patients will progress to AD.

widespread distribution of this imaging technology.

safe for use in humans (Koole, et al., 2009).

**2.3.2 [18F]Flutemetamol (3'-[18F]F-PiB or [18F]GE067)** 

this proof-of-concept study. After 80 minutes post injection, most regions of the neocortex showed a large difference in SUVRs (with the cerebellum as the reference region) between AD patients and healthy controls, except in the medial temporal cortex, which is more prone to NFT buildup than amyloid deposition, and the occipital cortex. This spatial distribution of [18F]flutemetamol uptake in AD patients closely resembles that typically seen in its parent molecule, [11C]PiB. Interestingly however, non-specific binding in white matter was more pronounced, but not statistically significant, in healthy controls injected with [18F]flutemetamol in comparison to when using [11C]PiB (Fodero-Tavoletti, et al., 2009).

While this study showed that [18F]flutemetamol PET imaging can be used to differentiate AD patients and healthy controls, 2 AD patients had particular regional SUVRs within the range seen in healthy controls. These results are comparable to previous [11C]PiB studies, in which 10-20% of clinically diagnosed AD patients did not show high cortical tracer uptake (W. E. Klunk, et al., 2004). Conversely, one healthy control had cortical SUVRs in line with those seen in AD patients. One possible explanation is that high white matter binding led to increased cortical values. The proportion of [18F]flutemetamol-positive healthy controls in this study, however, is comparable to the 10-30% of elderly healthy controls who have increased [11C]PiB brain uptake at levels indistinguishable from AD patients.

Based on the positive Phase I results, [18F]flutemetamol continued to be investigated in a clinical Phase II capacity (Vandenberghe, et al., 2010). Twenty-seven patients with clinically probable AD, 20 patients with amnestic MCI, 15 elderly healthy controls, and 10 younger healthy controls were used to determine the efficacy of blinded visual assessments of [18F]flutemetamol scans as well as to directly measure [18F]flutemetamol against its parent molecule [11C]PiB in terms of its discriminatory power. Researchers found that mean SUVRs in the frontal cortex, lateral temporal cortex, parietal cortex, anterior/posterior cingulate, and striatum were significantly higher in AD patients than in the elderly healthy controls. These results are consistent with the Phase I clinical study for [18F]flutemetamol. Based on blinded visual assessments of [18F]flutemetamol scans, 25 of 27 scans from AD subjects and 1 of 15 scans from the elderly healthy controls were PET-positive, corresponding to a sensitivity of 93.1% and a specificity of 93.3% against the clinical standard of truth. For MCI patients, 9 of 20 subjects were assigned to the high tracer uptake category. The proportion of [18F]flutemetamol-positive scans for MCI patients is comparable to that reported for [11C]PiB (Forsberg, et al., 2008). Additionally, investigators found that the test-retest variability ranged from 1 to 4%, which is lower than that reported for [11C]PiB. Most important to the validation of this radiotracer is that both visually and quantitatively, [18F]flutemetamol uptake was highly concordant with that of [11C]PiB for both AD and MCI patients. However, non-specific binding was greater with [18F]flutemetamol. Regardless, as was seen in Phase I clinical studies, high white matter uptake did not lead to any misclassifications of the scans by the visual readers.

Before clinical application, flutemetamol PET imaging needs to be tested against histopathology findings at autopsy. Thus, GE Healthcare is currently organizing and recruiting for an ongoing [18F]flutemetamol Phase III clinical study (Clinical Trial NCT01165554) that will include patients willing to undergo *post-mortem* studies. Results from this trial are pending (GEHC, Accessed 2011).
