When you buy ads direct from a publisher they usually charge a premium rate above what that ad inventory would sell for if it was sold through an automated ad auction. When Google launched site targeted AdSense ads years ago it was a cheap way for advertisers to buy specific audiences. Perfect for brand advertisers, but not as good for direct marketers. Why?
Advertising in Deep Dark Corners
It turns out that when you buy site targeted ads you typically first get exposure on the least valuable pages and least valuable ad units within a site. It makes sense that if all you want to do is advertise on a particular site then of course Google is going to sell you the inventory they struggled to monetize with their traditional keyword targeted PPC ads. So if the site has an offbeat category, or an AdSense ad block that is below the fold in the right column, those are the ad positions you are buying first.
Overpaying for Premium Exposure
You can buy your way into the more premium positions on the best pages too, but in order to do so you must bid high, which means you end up bidding at premium rates on the best pages, and you end up bidding too high for the backfill / remnant ad inventory on the least valuable pages. Not only are you losing money buying that off targeted backfill inventory, but you are competing against the most targeted ads on the most valuable pages, so it is hard to make money from buying site targeted ads unless they have a small niche site or are in a category where the ad market is exceptionally inefficient.
How to Buy Site Targeted Ads
There are some hacks around the issue of wasting money on site targeting though. The easiest of which is to look for footprints (URL, footer text, author name, etc.) on a site or the section of the site you want to advertise on and bid on those related keywords. If there is a section of the site that is irrelevant you can look for related footprints that are specific to those pages and use them as negative keywords.