Development of positron emission tomography β-amyloid plaque imaging agents

Abstract

For 100 years, β-amyloid (Aβ) plaques and neurofibrillary tangles (NFTs) have been recognized as the neuropathological hallmarks of Alzheimer's disease (AD), and their presence or absence could only be assessed postmortem using stains and dyes that identified these microscopic structures. Approximately 10 years ago, the first successful Aβ plaque-specific positron emission tomography (PET) imaging study was conducted in a living human subject clinically diagnosed with probable AD using the (11)C-labeled radiopharmaceutical Pittsburgh Compound B (PiB). Laboratory studies and preclinical evaluations to design PiB began a decade earlier than the first human PiB PET study and involved chemical modifications of different well-known dyes that bound specifically to the extended β-pleated sheets that comprise the fibrils of amyloid proteins such as Aβ plaques, NFTs, α-synuclein deposits, and prions. These preclinical studies were conducted in our laboratories at the University of Pittsburgh, starting with Congo red derivatives, followed by Chrysamine G derivatives, followed by X-series compounds, and finally with neutral derivatives of thioflavin-T. The in vitro and in vivo evaluations of the different derivatives as candidate PET radioligands for imaging Aβ plaques and neurofibrillary tangles in human brain are described in this review, along with the specific evaluation criteria by which the candidate radioligands were judged. Out of these studies came PiB, a PET radioligand that binds selectively and with high affinity to only fibrillar forms of Aβ. PiB has been used in many different human research protocols throughout the world and has demonstrated the usefulness of assessing the Aβ plaque status of subjects many years before the clinical diagnosis of probable AD. Recently, longer-lived (18)F-radiolabeled Aβ-selective radiopharmaceuticals have been developed. It is likely that the full clinical impact of these imaging agents will be realized by identifying presymptomatic subjects who would benefit from early drug treatments with future disease-modifying AD therapeutics.

Figure 1

Four generations of Congo Red and derivatives evaluated as potential PET amyloid imaging agents.

Figure 2

Potential amyloid-binding pharmacophores.

Figure 3

Structures of 3 neutral thioflavin-T analogs.

Figure 4

Relationship between normal mouse brain concentration (SUV is the standardized uptake value) for 11 ¹¹C-labeled BTA compounds 2 minutes after iv injection and the lipophilicity of the compounds as assessed by the logarithm of the reverse-phase HPLC–derived partition coefficient (logP_C18), which is proportional to the logD value of the derivatives.

Figure 5

Binding affinity of 3 neutral BTA compounds, the structures of which are shown in Figure 3, relative to thioflavin-T (ThT) for synthetic Aβ(1–40) fibrils.

Figure 6

Structure–affinity values for representative BTA analogs. The K_i values were determined using [³H]BTA-1 (R₆ = H, R4’ = NHCH₃) as the radioligand and synthetic Aβ(1–40) fibrils as the binding site protein.

Figure 7

Structure–clearance values for representative BTA analogs from normal mice brain. Values are the ratio of the %ID/g concentrations in mouse brain at 2 minutes after injection to the %ID/g concentrations at 30 minutes after injection.

Figure 8

First human PiB PET images obtained on February 14, 2002, by Bengt Långström and colleagues at the Uppsala University PET Centre from the first volunteer (mild AD, MMSE = 25; Reprinted with permission from Klunk and Mathis).

Figure 9

Structures of different PET radioligands selective for fibrillar Aβ.

Figure 10

Evolution from PiB of different Aβ-selective PET radioligands, with significant structural changes highlighted in gray shading.